CN101193869B

CN101193869B - Glucocortioid mimetics, methods of making them, pharmaceutical compositions, and uses thereof

Info

Publication number: CN101193869B
Application number: CN2006800205382A
Authority: CN
Inventors: 英戈·A·马格; 迈克尔·J·伯克; 马克·S·拉尔夫; 戴维·S·汤姆森; 阿卜杜拉金·哈马克; 詹妮弗·A·科瓦尔斯基; 乔尔格·M·本齐恩
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 2005-06-10
Filing date: 2006-06-08
Publication date: 2011-03-02
Anticipated expiration: 2026-06-08
Also published as: MX2007014811A; RU2007148225A; AR058006A1; TW200716573A; CA2610588A1; KR20080027828A; IL187976A0; NZ564696A; JP2008543780A; US20070060633A1; EP1893588A1; PE20070112A1; ZA200709430B; CN101193869A; BRPI0611620A2; WO2006135826A1; AU2006257861A1; US7622594B2

Abstract

Compounds of Formula (IA) and (IB) wherein R 1, R 2, R 3, A, B, C, D, and E are as defined herein, or a tautomer, prodrug, solvate, or salt thereof; pharmaceutical compositions containing such compounds, and methods of modulating the glucocorticoid receptor function and methods of treating disease-states or conditions mediated by the glucocorticoid receptor function or characterized by inflammatory, allergic, or proliferative processes in a patient using these compounds.

Description

Glucocorticosteroid stand-in, its preparation method, medical composition and its use

Technical field

The invention relates to glucocorticosteroid stand-in or part, the method for preparing described compound, its purposes on pharmaceutical composition, and in the purposes of regulating on the glucocorticoid receptor function, treatment reaches other purposes by the purposes on glucocorticoid receptor function institute's disease states mediated or the symptom in the patient of this treatment of needs.

Background of invention

Glucocorticosteroid is a kind of reflunomide, and it is for have the endogenous hormone of far-reaching effect for immunity system and multiple tract.It is by to for example inhibition of IL-1, IL-2, IL-6 and TNF of inflammatory factor, arachidonic acid metabolite is comprised the inhibition of prostaglandin(PG) and leukotriene, the lymphocytic exhaustion of T-, and the minimizing that adhesion molecule is expressed on the endotheliocyte, to suppress panimmunity and inflammatory function (P.J.Barnes, Clin.Sci., 1998 94, the 557-572 page or leaf; People such as P.J.Barnes, TrendsPharmacol.Sci., 1993, 14, the 436-441 page or leaf).Except these effects, glucocorticosteroid can stimulate the glucose in the liver to produce and proteinic katabolism, plays a role on ionogen and water balance, reduces calcium absorption, and is suppressed to bone cell function.

The anti-inflammatory of endogenous glucocorticosteroid and immunodepression activity have encouraged the exploitation of synthetic glucocorticoid derivative, comprise dexamethasone, prednisone and Prednisolone Acetate (L.Parente, Glucocorticoids, N.J.Goulding and R.J.Flowers (writing), Boston:Birkhauser, 2001, the 35-54 pages or leaves).These have found to be used in widely the treatment inflammatory, immunity and supersensitivity illness, comprise rheumatism, rheumatic arthritis for example, childhood sacroiliitis and ankylosing spondylitis, tetter, comprise psoriasis and pemphigus, the supersensitivity illness, comprise allergic rhinitis, atopic dermatitis and contact dermatitis, the lung symptom, comprise asthma and chronic obstruction tuberculosis (COPD), and other immunity and inflammatory diseases, comprise Crohn disease, ulcerative colitis, system lupus erythematosus, the chronic active hepatitis of autoimmunization, osteoarthritis, tendonitis and bursitis (J.Toogood Glucocorticoids, N.J.Goulding and R.J.Flowers (writing), Boston:Birkhauser, 2001, the 161-174 pages or leaves).It also repels in order to the help prevention in organ transplantation.

Unfortunately, except the desired therapeutic action of glucocorticosteroid, its purposes is also followed multiple disadvantageous side effect, and some of them can be serious and life-threatening.The development or deterioration and the osteoporosis that comprise change in fluid and the electrolyte balance, oedema, weight increase, hypertension, myasthenia, diabetes.Therefore, expect remain valid the simultaneously compound of antiinflammation of a kind of side effect that shows reduction especially, especially when treatment of chronic diseases.

The effect of glucocorticosteroid is under cell levels, by glucocorticoid receptor mediate (R.H.Oakley and J.Cidlowski, Glucocorticoids, N.J.Goulding and R.J.Flowers (writing), Boston:Birkhauser, 2001, the 55-80 pages or leaves).Glucocorticoid receptor is a member of relevant intracellular receptor kind on the structure, its when combining with part, can use as the transcription factor that can influence genetic expression (R.M.Evans, Science, 1988, 240, the 889-895 page or leaf).Other members of this steroid receptor family comprise mineralocorticoid, Progesterone, oestrogenic hormon and androgen receptor.About the mentioned effect of glucocorticosteroid, to the hormone that this receptor family is had an effect, the growth for health homeostasis, mineral metabolism, pressure effect and property feature has profound influence except above. Glucocorticoids, N.J.Goulding and R.J.Flowers (writing), Boston:Birkhauser, 2001, be in view of the above with its full text and for reference, so that the current state of this area to be described more well in this paper.

Be responsible for useful antiinflammation and do not want the molecular mechanism of side effect to be suggested (people such as S.Heck for example, EMBO J, 1994,17, the 4087-4095 page or leaf; People such as H.M.Reichardt, Cell, 1998, 93, the 531-541 page or leaf; People such as F.Tronche, Curr.Opin.In Genetics and Dev., 1998, 8, the 532-538 page or leaf).Many metabolism and cardiovascular side effects are considered to a kind of result who is called the transactivation process.In transactivation, part is displaced to after the nuclear in conjunction with glucocorticoid receptor, combines glucocorticosteroid response element (GRE) with the promoter region of side effect associated gene, for example, in the situation that increases the glucose generation, be enolpyruvate phosphate carboxyl kinases (PEPCK).Consequently these genetic transcription speed increase, and are recognized it and can cause the side effect of being found at last.Antiinflammation is considered to because due to a kind of process that is called trans-repression.Generally speaking, trans-repression is a kind of irrelevant process that combines with DNA, and it is because the inhibition of NF-kB and AP-1 institute mediated pathways causes, and causes the downward modulation of many inflammatories and immune mediator.In addition, think that many side effects of having found may be because due to the cross reactivity of present available glucocorticosteroid and other steroid receptors, particularly mineralocorticoid and progesterone receptor.

Therefore, possible discovery high selectivity and in conjunction with the time glucocorticoid receptor ligands of transactivation and trans-repression approach that can dissociate, have the therapeutical agent that reduces side effect thereby provide.Mensuration for the detection system of the effect of trans-activation and trans-repression be described (for example C.M.Bamberger and H.M.Schulte, Eur.J.Clin.Invest., 2000, 30(replenishing 3) 6-9 page or leaf).Can record by comprising that above mentioned person's binding affinity is made comparisons the selectivity of glucocorticoid receptor this acceptor and other steroid family receptors.

Glucocorticosteroid also can stimulate the generation of glucose in the liver by a kind of process that is called glyconeogenesis, thinks that in view of the above this process is to mediate by the transactivation incident.The glucose that increases produces type ii diabetes is more worsened, and therefore, selectivity suppresses the compound that glucose that glucocorticosteroid mediated produces, can in this indication, have the treatment usability (people such as J.E.Freidman, J.Biol.Chem., 1997, 272, the 31475-31481 page or leaf).

The novel part of glucocorticoid receptor has been described in science and the patent documentation.For example, the international open WO 04/093805 of PCT discloses selective spirocyclic shape glucocorticoid receptor modulator, can be used for potentially treating many inflammatory diseasess, comprises rheumatic arthritis and Crohn disease.The international open WO 04/026248 of PCT discloses octahydro-2H-naphtho-[1,2-f] indoles-4-carboxamide derivative, as the selectivity glucocorticoid receptor modulator, can be used for potentially treating many inflammatory diseasess, comprises rheumatic arthritis and Crohn disease.The international open WO 04/,075 840 of PCT discloses selectivity on-steroidal glucocorticoid receptor modulator, has the potential use as antiphlogistic, and about side effect, effect and toxicity, it has the advantage better than glucocorticoid ligands.The international open WO 03/086294 of PCT discloses 1H-benzo [f] indazole-5-radical derivative, as the selectivity glucocorticoid receptor modulator, can be used for potentially treating many inflammatory diseasess, comprises rheumatic arthritis and Crohn disease.The international open WO 03/061651 its corresponding U.S. Patent Application Publication 2005/0054700 of PCT discloses the on-steroidal part of glucocorticoid receptor, can be used for treating metabolism and inflammatory diseases potentially.The international open WO 99/33786 of PCT discloses the triphenyl propanamide compounds, has the potential use of treatment inflammatory diseases.The international open WO 00/66522 of PCT describes non-steroidal compound, as the selective modulator of glucocorticoid receptor, can be used for treating metabolism and inflammatory diseases potentially.The international open WO 99/41256 of PCT describes the Fourth Ring shape conditioning agent of glucocorticoid receptor, can be used for treatment immunity, autoimmunization and inflammatory diseases potentially.United States Patent (USP) 5,688,810 describe multiple non-steroidal compound, as the conditioning agent of glucocorticosteroid and other steroid receptors.The international open WO 99/63976 of PCT describes on-steroidal, liver selectivity glucocorticosteroid antagonist, can be used for treating diabetes potentially.The international open WO 00/32584 of PCT discloses the non-steroidal compound with antiphlogistic activity and the dissociation between anti-inflammatory and metabolism.The international open WO 98/54159 of PCT describes the substituted circularly acyl group anilid of on-steroidal, has the progesterone of mixing and androgenic activity.United States Patent (USP) 4,880,839 describe the acyl group anilid has progestogenic activity.Disclose the acyl group anilid with EP 253503 and have androgen antagonist character.The amides that the international open WO 97/27852 of PCT describes as farnesyl-protein matter transferase inhibitor.

2,2,2-three fluoro-1,1-is two-[1-(1-propyl group butyl)-1H-indoles-5-yl] ethanol by report as the by product of 5-bromo-1-(1-propyl group butyl)-1H-indoles and trifluoroacetic anhydride condensation under the metal halogen give-and-take conditions (people such as H.Takami, Heterocycles, 1999 51, the 1119-1124 page or leaf).4,4,4-three fluoro-3-hydroxyl-3-[1-(1-propyl group butyl)-1H-indoles-5-yl] the revealed conduct of ethyl butyrate is in bromoethyl acetate and 2,2,2-three fluoro-1-[1-(1-propyl group butyl)-1H-indoles-5-yl] the product (people such as H.Takami of Reformatsky reaction between ethyl ketone, Med.Chem.Res.EN 1999,9 (4), the 239-248 page or leaf).

In conjunction with the meeting of discovery and the interactive compound of glucocorticoid receptor in detecting, can be agonist or antagonist.The agonist character of compound can assessment in above-mentioned transactivation or trans-repression detection.By available glucocorticoid medicine under effect that shows on inflammatory and the Immunological diseases and disadvantageous side effect thereof, still need novel glucocorticoid receptor agonist, it has the selectivity with respect to other members of steroid receptor family, and transactivation and trans-repression is active dissociates.Perhaps, can find that compound has antagonistic activity.As indicated above, glucocorticosteroid stimulates the generation of glucose in the liver.Glucose by the excessive increase that causes of glucocorticosteroid produces, and existing diabetes are more worsened, or triggers the diabetes of hiding.Therefore, be found to be part, can be used for especially treating or prevent diabetes into the glucocorticoid receptor of antagonist.

Summary of the invention

The present invention relates to formula (IA) compound

Wherein:

R ¹Be aryl, heteroaryl or C ₃-C ₇Cycloalkyl, each group are randomly independent to be replaced by one to three substituting group, and described substituting group is selected from C ₁-C ₃Alkyl, hydroxyl, halogen, oxo, methoxyl group, amino, wherein nitrogen-atoms is randomly independent of methyl list-or two replace, or methylthio group (thiomethyl) wherein sulphur atom randomly be oxidized to sulfoxide or sulfone;

R ²Be hydrogen or halogen;

A and B independently are CH or N separately;

C and E independently be separately chemical bond or-CH ₂-;

D is CR ⁴R ⁵-, R wherein ⁴For-CF ₃, and R ⁵For-OH; And

R ³Be C ₁-C ₆Alkyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl, heterocyclic radical, NR ⁶R ⁷, OR ⁸Or SR ⁹, each group is randomly independent to be replaced by one to three substituting group,

Wherein, R ³Each substituting group be aryl, heteroaryl, heterocyclic radical, C independently ₁-C ₅Alkyl, C ₁-C ₅Thiazolinyl, cycloalkyl, cycloalkenyl group, acyl group, carbalkoxy, C ₁-C ₅Alkanoyloxy, C ₁-C ₅Alkyloyl, aroyl, C ₁-C ₅Alkyl amide, alkyl amino-carbonyl, dialkyl amino carbonyl, aminocarboxyl oxygen base, C ₁-C ₅Alkyl amino carbonyl oxy, C ₁-C ₅Dialkyl amino carbonyl oxy, C ₁-C ₅Alkyl amide, C ₁-C ₅Alkoxycarbonyl amido, C ₁-C ₅Alkyl sulfonyl-amino, amino-sulfonyl, C ₁-C ₅Alkyl amino sulfonyl, C ₁-C ₅Dialkyl amino sulfonyl, C ₁-C ₅Alkoxyl group, aryloxy, halogen, hydroxyl, oxo, cyano group, trifluoromethyl, nitro, carboxyl, aminocarboxyl, amino, wherein nitrogen-atoms is randomly independent of C ₁-C ₅The alkyl list-or two replacements, or C ₁-C ₅Alkylthio wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,

R wherein ³Each substituting group randomly independently replaced by one to three substituting group, described substituting group is selected from aryl, heteroaryl, heterocyclic radical, acyl group, C ₁-C ₅Alkyl, C ₁-C ₅Alkanoyloxy, C ₁-C ₅Alkyloyl, C ₁-C ₅Alkyl amide, alkyl amino-carbonyl, dialkyl amino carbonyl, C ₁-C ₅Alkyl sulfonyl-amino, amino-sulfonyl, C ₁-C ₅Alkyl amino sulfonyl, C ₁-C ₅Dialkyl amino sulfonyl, C ₁-C ₅Alkoxyl group, C ₁-C ₅Cycloalkyl, aryloxy, halogen, hydroxyl, oxo, cyano group, trifluoromethyl, nitro, aminocarboxyl, amino, wherein nitrogen-atoms is randomly independent of C ₁-C ₅The alkyl list-or two replacements, or C ₁-C ₅Alkylthio wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,

R wherein ⁶Be hydrogen or C ₁-C ₃Alkyl, and

R ⁷, R ⁸And R ⁹Independent separately is C ₁-C ₅Alkyl, C ₁-C ₅Thiazolinyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl or heterocyclic radical, each group are randomly independent to be replaced by one to three substituting group,

R wherein ⁷, R ⁸And R ⁹Each substituting group be heteroaryl, heterocyclic radical, C independently ₁-C ₅Alkyl, cycloalkyl, cycloalkenyl group, acyl group, carbalkoxy, C ₁-C ₅Alkanoyloxy, C ₁-C ₅Alkyloyl, aroyl, C ₁-C ₅Alkyl amide, alkyl amino-carbonyl, dialkyl amino carbonyl, aminocarboxyl oxygen base, C ₁-C ₅Alkyl amino carbonyl oxy, C ₁-C ₅Dialkyl amino carbonyl oxy, C ₁-C ₅Alkyl amide, C ₁-C ₅Alkoxycarbonyl amido, C ₁-C ₅Alkyl sulfonyl-amino, amino-sulfonyl, C ₁-C ₅Alkyl amino sulfonyl, C ₁-C ₅Dialkyl amino sulfonyl, C ₁-C ₅Alkoxyl group, aryloxy, halogen, hydroxyl, oxo, cyano group, trifluoromethyl, nitro, aminocarboxyl, amino, wherein nitrogen-atoms is randomly independent of C ₁-C ₅The alkyl list-or two replacements, or C ₁-C ₅Alkylthio wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,

R wherein ⁷, R ⁸And R ⁹Each substituting group randomly independently replaced by one to three substituting group, described substituting group is selected from heteroaryl, heterocyclic radical, acyl group, C ₁-C ₅Alkyl,

C ₁-C ₅Alkyl amide, alkyl amino-carbonyl, dialkyl amino carbonyl, C ₁-C ₅Alkyl sulfonyl-amino, amino-sulfonyl, C ₁-C ₅Alkyl amino sulfonyl, C ₁-C ₅Dialkyl amino sulfonyl, C ₁-C ₅Alkoxyl group, aryloxy, halogen, hydroxyl, oxo, cyano group, trifluoromethyl, nitro, aminocarboxyl, amino, wherein nitrogen-atoms is randomly independent of C ₁-C ₅The alkyl list-or two replacements, or C ₁-C ₅Alkylthio wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,

Or its tautomer, prodrug, solvate or salt.

An aspect of of the present present invention comprises formula (IA) compound, wherein:

R ¹Be aryl or heteroaryl, each group is randomly independent to be replaced by one to three substituting group, and described substituting group is selected from hydroxyl, halogen or oxo;

R ²Be hydrogen; And

C is a chemical bond, and E be chemical bond or-CH ₂-,

Or its tautomer, prodrug, solvate or salt.

R ¹Be phenyl, randomly replaced by one to three halogen group;

A is N;

B is CH; And

R ³Be phenyl, naphthyl, pyridyl, quinoline, isoquinoline 99.9, indoles, azaindole, thionaphthene, cumarone, 2,3-dihydro-1,4-benzo dioxine, 1,3-benzodioxole, 3,4-dihydro-2H-1,4-benzo

Piperazine, 1,2,3,4-tetrahydroisoquinoline, N-ethyl-N '-methylbenzene-1,2-diamines, 1,2,3,4-tetrahydroquinoline, NR ⁶R ⁷, OR ⁸Or SR ⁹Group, each group are randomly independent to be replaced by one to three substituting group,

R wherein ³Each substituting group be C independently ₁-C ₅Alkyl, heteroaryl, heterocyclic radical, acyl group, C ₁-C ₅Alkoxyl group, halogen, hydroxyl, oxo, cyano group, trifluoromethyl, aminocarboxyl, amino, wherein nitrogen-atoms is randomly independent of C ₁-C ₅The alkyl list-or two replacements, C ₁-C ₅Thiazolinyl, carboxyl or C ₁-C ₅Alkylthio wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,

R wherein ³Each substituting group randomly independently replaced by one to three substituting group, described substituting group is selected from heterocyclic radical, C ₁-C ₅Alkyl, C ₁-C ₅Alkoxyl group, halogen, hydroxyl, oxo, cyano group, trifluoromethyl, aminocarboxyl, amino, wherein nitrogen-atoms is randomly independent of C ₁-C ₅The alkyl list-or two replacements, or C ₁-C ₅Alkylthio wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,

R wherein ⁶Be hydrogen or methyl, and

R ⁷, R ⁸And R ⁹Independent separately is phenyl, naphthyl, pyridyl, pyrimidyl, quinoline, isoquinoline 99.9 or indyl, and each group is randomly independent to be replaced by one to three substituting group,

R wherein ⁷, R ⁸And R ⁹Each substituting group be heterocyclic radical, C independently ₁-C ₅Alkyl, cycloalkyl, acyl group, C ₁-C ₅Alkoxyl group, halogen, hydroxyl, oxo, cyano group, trifluoromethyl, aminocarboxyl, amino, wherein nitrogen-atoms is randomly independent of C ₁-C ₅The alkyl list-or two replacements, or C ₁-C ₅Alkylthio wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,

The one side of above-mentioned specific embodiments comprises formula (IA) compound, wherein:

Piperazine, 1,2,3,4-tetrahydroisoquinoline, N-ethyl-N '-methylbenzene-1,2-diamines or 1,2,3, the 4-tetrahydroquinoline,

R wherein ³Each substituting group be C independently ₁-C ₅Alkyl, C ₁-C ₅Thiazolinyl, carboxyl, acyl group, C ₁-C ₅Alkoxyl group, halogen, hydroxyl, oxo, cyano group, trifluoromethyl, aminocarboxyl, amino, wherein nitrogen-atoms is randomly independent of C ₁-C ₅The alkyl list-or two replacements, or C ₁-C ₅Alkylthio wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,

R wherein ³Each substituting group randomly independently replaced by one to three substituting group, described substituting group is selected from C ₁-C ₅Alkyl, halogen, hydroxyl, oxo, cyano group, trifluoromethyl, aminocarboxyl, amino, wherein nitrogen-atoms is randomly independent of C ₁-C ₅The alkyl list-or two replacements, or

C ₁-C ₅Alkylthio wherein sulphur atom randomly is oxidized to sulfoxide or sulfone, or its tautomer, prodrug, solvate or salt.

The representative compounds of the formula according to the present invention (IA) is to enclose with literary composition with Table I A, and its intermediate hurdles A is the compound title according to standardized denomination, and hurdle B is its corresponding chemical structure.

Preferred formula (IA) compound comprises following:

1-biphenyl-3-base-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(3, the 4-difluorophenyl)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(3, the 5-difluorophenyl)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(3-chloro-5-fluorophenyl)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(4-chloro-3-aminomethyl phenyl)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(3-chloro-phenyl-)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(3-chloro-4-fluorophenyl)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(4-chloro-3-fluorophenyl)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(3, the 5-dichlorophenyl)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-naphthalene-1-base-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(3-fluorophenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(4-methylnaphthalene-1-yl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(2,3-dihydrobenzo [1,4] dioxine-6-yl)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(3, the 4-dichlorophenyl)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(4-fluorophenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(3-fluoro-4-aminomethyl phenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-benzo [1,3] dioxole-5-base-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-1,3-benzodioxole-4-base-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(2,2-two fluoro-1,3-benzodioxole-4-yl)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(4-chloro-phenyl-)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-phenyl-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl)-1-(2) ethanol;

2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl)-1-(2,4, the 6-trimethylphenyl) ethanol;

1-(the 4-tertiary butyl-2,6-3,5-dimethylphenyl)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(3-p-methoxy-phenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(3, the 5-3,5-dimethylphenyl)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(4-methoxyl group-3,5-3,5-dimethylphenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(4-p-methoxy-phenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(3, the 4-3,5-dimethylphenyl)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(3-fluoro-4-p-methoxy-phenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(5-fluoro-2-p-methoxy-phenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(2, the 5-Dimethoxyphenyl)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(2-morpholine-4-ylmethyl phenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-biphenyl-2-base-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(4-fluoronaphthalene-1-yl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(4-dimethylamino naphthalene-1-yl)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(2-methylnaphthalene-1-yl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(2-methoxynaphthalene-1-yl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-naphthalene-2-base-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl)-1-quinolyl-4 ethanol;

2,2,2-three fluoro-1-(1H-indoles-4-yl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1,1,1-three fluoro-3-indoles-1-base-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1-[3,3,3-three fluoro-2-hydroxyl-2-(1-phenyl-1H-indazole-5-yl) propyl group]-1H-indoles-3-nitrile;

3-(3,4-dihydro-2H-quinoxaline-1-yl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(3,4-dihydro-2H-quinoline-1-yl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-3-(3-fluorophenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-3-phenyl-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-2-phenyl-3-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-thiophenyl propan-2-ol;

1,1,1-three fluoro-3-(4-fluorobenzene sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-3-phenoxy group-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(3,5-two fluorophenoxies)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(3,5-dimethoxy phenoxy group)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1-benzo [b] thiene-3-yl--2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl)-1-quinolyl-4 ethanol;

2,2,2-three fluoro-1-isoquinolyl-1-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-benzo [b] thiene-3-yl--2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-phenylethyl alcohol;

1-(3-chloro-4-fluorophenyl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-naphthalene-1-base ethanol;

2,2,2-three fluoro-1-(4-fluoronaphthalene-1-yl)-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(4-methylnaphthalene-1-yl) ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-Methyl-1H-indole-4-yl) ethanol;

1-1,3-benzodioxole-4-base-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

1-(2,2-two fluoro-1,3-benzodioxole-4-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

2,2,2-three fluoro-1-phenyl-1-(1-phenyl-1H-benzotriazole-5-yl) ethanol;

2,2,2-three fluoro-1-(6-fluorine pyridine-2-yl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

3-(3-chloro-2-fluorophenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(4-chloro-3-fluorophenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(4-chloro-2-fluorophenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1H-indoles-7-yl) ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-Methyl-1H-indole-7-yl) ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-Methyl-1H-indole-5-yl) ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-Methyl-1H-indole-6-yl) ethanol;

4-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl } indoles-1-formic acid tertiary butyl ester;

1-(3-aminophenyl)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

N-{3-[2,2,2-three fluoro-1-hydroxyl-1-(1-phenyl-1H-indazole-5-yl) ethyl] phenyl } ethanamide;

1-methyl-4-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-the 1H-quinoline-2-one-;

1-(1-allyl group-1H-indoles-4-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

3-(4-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl } indoles-1-yl) propane-1, the 2-glycol;

3-hydroxyl-4-(4-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl } indoles-1-yl) butyronitrile;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-[1-(2-hydroxyethyl)-1H-indoles-4-yl] ethanol;

2-(4-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl } indoles-1-yl) ethanamide;

N-methyl-2-(4-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl } indoles-1-yl) ethanamide;

1-[1-(2-cyclopropyl-2-hydroxyethyl)-1H-indoles-4-yl]-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

1-(7-bromo-1-Methyl-1H-indole-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-formic acid methyl ester;

1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-formic acid;

1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-benzoic acid amides;

1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-formic acid methyl nitrosourea;

1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-formic acid (2-cyano ethyl) acid amides;

1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-formic acid (2-methoxy ethyl) acid amides;

1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-formic acid (2-methoxy ethyl) methyl nitrosourea;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-methyl-7-nitro-1H-indol-3-yl) ethanol;

1-(7-amino-1-Methyl-1H-indole-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-formic acid formamyl methyl nitrosourea;

1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-formic acid Cyanomethyl amides;

1-(1-allyl group-1H-indol-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

N-(1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-yl) Toluidrin;

3-(3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl } indoles-1-yl) propane-1, the 2-glycol;

1-benzyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-formic acid methyl ester;

2-(3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl } indoles-1-yl) ethanamide;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-[1-(2-hydroxyethyl)-1H-indol-3-yl] ethanol;

N-methyl-2-(3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl } indoles-1-yl) ethanamide;

N-cyano methyl-2-(3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl } indoles-1-yl) ethanamide;

N-carbamyl ylmethyl-2-(3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl } indoles-1-yl) ethanamide;

1-morpholine-4-base-2-(3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl } indoles-1-yl) ethyl ketone;

1-allyl group-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-formic acid methyl ester;

1-allyl group-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-benzoic acid amides;

1-(2, the 3-dihydroxypropyl)-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-benzoic acid amides;

1-(1-allyl group-1H-indol-3-yl)-2,2,2-three fluoro-1-(1-p-tolyl-1H-indazole-5-yl) ethanol;

3-{3-[2,2,2-three fluoro-1-hydroxyl-1-(1-p-tolyl-1H-indazole-5-yl) ethyl] indoles-1-yl } propane-1, the 2-glycol;

2,2,2-three fluoro-1-(4-fluoronaphthalene-1-yl)-1-(1-phenyl-1H-indoles-5-yl) ethanol;

2,2,2-three fluoro-1-naphthalene-1-base-1-(1-phenyl-1H-indoles-5-yl) ethanol;

1-(3, the 4-dichlorophenyl)-2,2,2-three fluoro-1-(1-pyridine-2-base-1H-indazole-5-yl) ethanol;

1-(3-chloro-phenyl-)-2,2,2-three fluoro-1-(1-pyridine-2-base-1H-indazole-5-yl) ethanol;

1-(3, the 4-difluorophenyl)-2,2,2-three fluoro-1-(1-pyridine-2-base-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-phenyl-1-(1-pyridine-2-base-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-[1-(2-fluorophenyl)-1H-indazole-5-yl]-the 1-phenylethyl alcohol;

2,2,2-three fluoro-1-[1-(2-fluorophenyl)-1H-indazole-5-yl]-1-naphthalene-1-base ethanol;

2,2,2-three fluoro-1-(4-fluoronaphthalene-1-yl)-1-[1-(2-fluorophenyl)-1H-indazole-5-yl] ethanol;

2,2,2-three fluoro-1-phenyl-1-(1-p-tolyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-[1-(4-p-methoxy-phenyl)-1H-indazole-5-yl]-the 1-phenylethyl alcohol;

2,2,2-three fluoro-1-phenyl-1-(1-o-tolyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-naphthalene-1-base-1-(1-o-tolyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(4-fluoronaphthalene-1-yl)-1-(1-o-tolyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(5-fluoro-1H-indol-3-yl)-1-(1-p-tolyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(5-fluoro-1H-indol-3-yl)-1-[1-(2-fluorophenyl)-1H-indazole-5-yl] ethanol;

2,2,2-three fluoro-1-(5-fluoro-1H-indol-3-yl)-1-[1-(4-p-methoxy-phenyl)-1H-indazole-5-yl] ethanol;

2,2,2-three fluoro-1-(5-fluoro-1H-indol-3-yl)-1-(1-pyridine-2-base-1H-indazole-5-yl) ethanol;

3-[2,2,2-three fluoro-1-hydroxyl-1-(1-phenyl-1H-indazole-5-yl) ethyl] phenol;

2,2,2-three fluoro-1-(4-fluoro-3-hydroxymethyl phenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

4-[2,2,2-three fluoro-1-hydroxyl-1-(1-phenyl-1H-indazole-5-yl) ethyl] phenol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(5-methoxyl group-4-Methyl-1H-indole-3-yl) ethanol;

1-(4-chloro-1H-indol-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(6-methoxyl group-1H-indol-3-yl) ethanol;

1-(2,5-dimethyl-1H-indol-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(7-methoxyl group-1H-indol-3-yl) ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1H-indol-3-yl) ethanol;

1-(6-bromo-1H-indol-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

1-(7-bromo-1H-indol-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

1-(5-bromo-1H-indol-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(5-Methyl-1H-indole-3-yl) ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(2-Methyl-1H-indole-3-yl) ethanol;

1-(6-chloro-1H-indol-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

1-(5-chloro-1H-indol-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

1-(4-bromo-1H-indol-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

2,2,2-three fluoro-1-(5-fluoro-1H-indol-3-yl)-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

2,2,2-three fluoro-1-(4-fluoro-1H-indol-3-yl)-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

2,2,2-three fluoro-1-(6-fluoro-1H-indol-3-yl)-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(5-methoxyl group-1H-indol-3-yl) ethanol;

2,2,2-three fluoro-1-(7-fluoro-1H-indol-3-yl)-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(6-Methyl-1H-indole-3-yl) ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(7-Methyl-1H-indole-3-yl) ethanol;

3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-5-nitrile;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-Methyl-1H-indole-3-yl) ethanol;

1-(6-bromo-1-Methyl-1H-indole-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-the 1H-indole-6-carbonitrile;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-methyl-6-pyridin-3-yl-1H-indol-3-yl) ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-methyl-6-pyridin-4-yl-1H-indol-3-yl) ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-methyl-6-morpholine-4-base-1H-indol-3-yl) ethanol;

1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-6-formic acid methyl ester;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(6-furans-2-base-1-Methyl-1H-indole-3-yl) ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-methyl-6-pyrimidine-5-base-1H-indol-3-yl) ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-{6-[(2-methoxy ethyl) methylamino]-1-Methyl-1H-indole-3-yl } ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-[6-(2-methoxy ethyl amino)-1-Methyl-1H-indole-3-yl] ethanol;

The 1-{6-[(2-dimethyl aminoethyl) methylamino]-1-Methyl-1H-indole-3-yl }-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-methyl-5-morpholine-4-base-1H-indol-3-yl) ethanol;

1-[6-(2-dimethyl aminoethyl amino)-1-Methyl-1H-indole-3-yl]-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

1-[5-(2-dimethyl aminoethyl amino)-1-Methyl-1H-indole-3-yl]-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-methyl-6-tetramethyleneimine-1-base-1H-indol-3-yl) ethanol;

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-methyl-5-tetramethyleneimine-1-base-1H-indol-3-yl) ethanol;

1-[6-bromo-1-(4-methoxy-benzyl)-1H-indol-3-yl]-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol;

N-carbamyl ylmethyl-N-methyl-2-{3-[2,2,2-three fluoro-1-hydroxyl-1-(1-p-tolyl-1H-indazole-5-yl) ethyl] indoles-1-yl } ethanamide;

N-carbamyl ylmethyl-2-{3-[2,2,2-three fluoro-1-hydroxyl-1-(1-p-tolyl-1H-indazole-5-yl) ethyl] indoles-1-yl } ethanamide;

N-(2-methoxy ethyl)-N-methyl-2-{3-[2,2,2-three fluoro-1-hydroxyl-1-(1-p-tolyl-1H-indazole-5-yl) ethyl] indoles-1-yl } ethanamide;

N-(2-methoxy ethyl)-2-{3-[2,2,2-three fluoro-1-hydroxyl-1-(1-p-tolyl-1H-indazole-5-yl) ethyl] indoles-1-yl } ethanamide;

N-cyano methyl-2-{3-[2,2,2-three fluoro-1-hydroxyl-1-(1-p-tolyl-1H-indazole-5-yl) ethyl] indoles-1-yl } ethanamide;

N-methyl-2-{3-[2,2,2-three fluoro-1-hydroxyl-1-(1-p-tolyl-1H-indazole-5-yl) ethyl] indoles-1-yl } ethanamide;

2-{3-[2,2,2-three fluoro-1-hydroxyl-1-(1-p-tolyl-1H-indazole-5-yl) ethyl] indoles-1-yl } ethanamide;

2,2,2-three fluoro-1-[1-(2-hydroxyethyl)-1H-indol-3-yl]-1-(1-p-tolyl-1H-indazole-5-yl) ethanol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(2-4-trifluoromethylphenopendant) propan-2-ol;

3-(2-chloro-3,5-two fluorophenoxies)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(5-chloro-2-methylphenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(4-bromine phenoxy group)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-3-(indane-5-base oxygen)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(2,4, the 6-Trichlorophenoxy) propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(2,4,6-trimethylammonium phenoxy group) propan-2-ol;

3-(3-bromine phenoxy group)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(2,4 dichloro benzene oxygen base)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(2-bromine phenoxy group)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(3-4-trifluoromethylphenopendant) propan-2-ol;

3-(2-chloro-5-methylphenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(4-4-trifluoromethylphenopendant) propan-2-ol;

1,1,1-three fluoro-3-(naphthalene-2-base oxygen)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(2-chlorophenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(4-chlorophenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(2-chloro-4-methylphenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(4-chloro-2-fluorophenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-3-(4-fluoro-2-methylphenoxy)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(2,3,4-trifluoromethoxy phenoxy base) propan-2-ol;

1,1,1-three fluoro-3-(7-methoxynaphthalene-2-base oxygen)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(2-bromo-5-fluorophenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-3-(2-fluoro-5-4-trifluoromethylphenopendant)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(4-bromo-3-methylphenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-3-(2-fluoro-5-methylphenoxy)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-3-(4-methylthio group phenoxy group)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(3-chlorophenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-o-tolyloxy propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-m-tolyloxy propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-p-tolyloxy propan-2-ol;

3-(2, the 6-dimethyl phenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(2, the 6-dichlorophenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(3, the 5-dichlorophenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-3-(naphthalene-1-base oxygen)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-3-(isoquinoline 99.9-7-base oxygen)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(2-Trifluoromethyl phenyl ether oxygen base) propan-2-ol;

1,1,1-three fluoro-3-(4-phenyl amino phenoxy group)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(3-chloro-4-methylphenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-3-(3-fluoro-5-4-trifluoromethylphenopendant)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-3-(2-methylthio group phenoxy group)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(4-chloro-3-4-trifluoromethylphenopendant)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(2,4-two chloro-6-methylphenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(2,6-two chloro-4-methylphenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-methoxyl group-4-[3,3,3-three fluoro-2-hydroxyl-2-(1-phenyl-1H-indazole-5-yl) propoxy-] the phenylformic acid ethyl ester;

1,1,1-three fluoro-3-(4-imidazoles-1-phenoxyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(3-chloro-5-5-flumethiazine-2-base oxygen)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(5,6,7,8-naphthane-1-base oxygen) propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(5,6,7,8-naphthane-2-base oxygen) propan-2-ol;

2-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxyl propoxy-} benzonitrile;

3-(2-bromine phenoxy group)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

3-(2-chlorophenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

3-(2,4 dichloro benzene oxygen base)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2,4, the 6-Trichlorophenoxy) propan-2-ol;

3-(2-chloro-5-methylphenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

3-(2, the 6-dichlorophenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2-4-trifluoromethylphenopendant) propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-o-tolyloxy propan-2-ol;

3-(2, the 4-dimethyl phenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2,4,6-trimethylammonium phenoxy group) propan-2-ol;

3-(2, the 6-dimethyl phenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

3-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxyl propoxy-} benzonitrile;

3-(3-bromine phenoxy group)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-3-(3-fluorophenoxy)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

3-(3,5-two fluorophenoxies)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

3-(3-chlorophenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

3-(3, the 5-dichlorophenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-m-tolyloxy propan-2-ol;

3-(3, the 5-dimethyl phenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

4-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxyl propoxy-} benzonitrile;

3-(4-bromine phenoxy group)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-3-(4-fluorophenoxy)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

3-(4-chlorophenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(4-4-trifluoromethylphenopendant) propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-p-tolyloxy propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(indane-5-base oxygen) propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(naphthalene-1-base oxygen) propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(naphthalene-2-base oxygen) propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(quinoline-5-base oxygen) propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(quinoline-8-base oxygen) propan-2-ol;

3-(2,4 difluorobenzene oxygen base)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(quinoline-7-base oxygen) propan-2-ol;

3-methoxyl group-4-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxyl propoxy-} the phenylformic acid ethyl ester;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(4-phenyl amino phenoxy group) propan-2-ol;

N-(4-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxyl propoxy-} phenyl) butyramide;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(4-trifluoromethylthio phenoxy group) propan-2-ol;

5-ethanoyl-2-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxyl propoxy-} benzoic acid methyl ester;

3-(2-bromo-5-fluorophenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2,3,4-trifluoromethoxy phenoxy base) propan-2-ol;

3-(2,5-two fluorophenoxies)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

3-(4-chloro-3-4-trifluoromethylphenopendant)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

3-(acridine-4-base oxygen)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(3-morpholine-4-phenoxyl) propan-2-ol;

2-chloro-4-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxyl propoxy-} benzonitrile;

3-(4-bromo-2-methylphenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

3-(3-chloro-4-methylphenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

3-(5-chloro-2-methylphenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2,3,6-trifluoromethoxy phenoxy base) propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2,4,5-trifluoromethoxy phenoxy base) propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2,4,6-trifluoromethoxy phenoxy base) propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2-fluoro-5-4-trifluoromethylphenopendant) propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(3-fluoro-5-4-trifluoromethylphenopendant) propan-2-ol;

3-(2-chloro-4-methylphenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

3-(4-chloro-2-fluorophenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-3-(4-fluoro-2-methylphenoxy)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-3-(2-fluoro-6-methoxyl group phenoxy group)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

3-(2-chloro-3,5-two fluorophenoxies)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2,3,5-trifluoromethoxy phenoxy base) propan-2-ol;

3-(4-bromo-3-methylphenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(6-methoxynaphthalene-2-base oxygen) propan-2-ol;

3-(2,6-two chloro-4-methylphenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

4-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxyl propoxy-} indan-1-one;

5-bromo-2-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxyl propoxy-} benzonitrile;

1,1,1-three fluoro-3-(2-fluoro-5-methylphenoxy)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

5-chloro-2-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxyl propoxy-} benzonitrile;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2-Trifluoromethyl phenyl ether oxygen base) propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(isoquinoline 99.9-7-base oxygen) propan-2-ol;

3-(3,4-dimethoxy phenoxy group)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(3-Trifluoromethyl phenyl ether oxygen base) propan-2-ol;

3-(2,4-two chloro-6-methylphenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-3-(2-isopropyl benzene sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(pyridine-2-base sulfenyl) propan-2-ol;

3-(4-ethylbenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

4-methyl-7-[3,3,3-three fluoro-2-hydroxyl-2-(1-phenyl-1H-indazole-5-yl) rosickyite base]-the 1-chromen-2-one;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(3-trifluoromethyl thiophenyl) propan-2-ol;

3-(2,3-dichlorobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(4-trifluoromethyl thiophenyl) propan-2-ol;

1,1,1-three fluoro-3-(naphthalene-1-base sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(4-thiophene-2-yl pyrimidines-2-base sulfenyl) propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(4-phenyl pyrimidine-2-base sulfenyl) propan-2-ol;

3-[4-(4-chloro-phenyl-) pyrimidine-2-base sulfenyl]-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

6-methyl-2-[3,3,3-three fluoro-2-hydroxyl-2-(1-phenyl-1H-indazole-5-yl) rosickyite base]-4-trifluoromethyl nicotine nitrile (nicotinonitrile);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(5-5-flumethiazine-2-base sulfenyl) propan-2-ol;

3-(2-chloro-4-fluorobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(4-trifluoromethoxy thiophenyl) propan-2-ol;

3-(4-bromo-2-trifluoromethoxy thiophenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-3-(4-anisole sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(quinoline-2-base sulfenyl) propan-2-ol;

3-(4-chlorobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(pyrimidine-2-base sulfenyl) propan-2-ol;

3-(4,6-dimethyl pyrimidine-2-base sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(3,4-dichlorobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(2,5-dichlorobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(pyridin-4-yl sulfenyl) propan-2-ol;

1,1,1-three fluoro-3-(3-anisole sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-3-(2-anisole sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(3-chlorobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(2,6-dichlorobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(3-bromobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(3,4-dimethyl benzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-3-(naphthalene-2-base sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-3-(2-fluorobenzene sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-3-(3-fluorobenzene sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(2,5-dimethoxy thiophenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(2,4-dimethyl benzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(2,5-dimethyl benzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(2,6-dimethyl benzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(2-ethylbenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

2-[3,3,3-three fluoro-2-hydroxyl-2-(1-phenyl-1H-indazole-5-yl) rosickyite base] benzoic acid methyl ester;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(4-trifluoromethyl pyrimidine-2-base sulfenyl) propan-2-ol;

3-(3,5-dimethyl benzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(3,5-couple-the trifluoromethyl thiophenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(2,4 difluorobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-3-(4-isopropyl benzene sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(2,4 dichloro benzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(3,5-dichlorobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(2-trifluoromethyl thiophenyl) propan-2-ol;

3-(3,4-difluoro thiophenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(3-phenetole sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(4-tert.-butylbenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

N-{4-[3,3,3-three fluoro-2-hydroxyl-2-(1-phenyl-1H-indazole-5-yl) rosickyite base] phenyl } ethanamide;

3-(4-bromobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-3-(4-nitrophenylsulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-o-tolyl sulfenyl propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-m-tolyl sulfenyl propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-p-tolyl sulfenyl propan-2-ol;

3-(3-chloro-4-fluorobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(3,4-dimethoxy thiophenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(the 5-tertiary butyl-2-methylbenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(2,4,6-Three methyl Benzene sulfenyl) propan-2-ol;

1,1,1-three fluoro-3-(4-methylthio phenyl sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(2-chloro-6-methylbenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

3-(2-tert.-butylbenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(3-5-flumethiazine-2-base sulfenyl) propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(3-trifluoromethoxy thiophenyl) propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(4-skatole-1-yl) propan-2-ol;

3-[2-(4-chloro-phenyl-) indoles-1-yl]-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

(1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-the 1H-indol-3-yl) acetonitrile;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(6-methoxyl group indoles-1-yl) propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(5-skatole-1-yl) propan-2-ol;

3-(4-benzyloxy indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

3-(4-chloro-indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

3-(6-chloro-indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(6-skatole-1-yl) propan-2-ol;

1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-1H-indoles-4-formic acid methyl ester;

1,1,1-three fluoro-3-(6-fluoro indole-1-yl)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-1H-indole-3-carboxylic acid methyl ester;

2,2,2-three fluoro-1-(1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-the 1H-indol-3-yl) ethyl ketone;

1,1,1-three fluoro-3-(4-fluoro indole-1-yl)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

N-[2-(5-methoxyl group-1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-the 1H-indol-3-yl) ethyl] ethanamide;

3-(7-bromo indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

3-(7-chloro-indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

(the 2-methyl isophthalic acid-3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-the 1H-indol-3-yl) the acetate ethyl ester;

1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-1H-indole-5-carboxylic acid methyl ester;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2-methyl-5-nitro indoles-1-yl) propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-[2-(4-fluorophenyl) indoles-1-yl] propan-2-ol;

3-(4-bromo indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

3-(6-bromo indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

3-(3-dimethylaminomethyl-6-methoxyl group indoles-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

(5-methoxyl group-1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-the 1H-indol-3-yl) acetonitrile;

(5-benzyloxy-1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-the 1H-indol-3-yl) acetonitrile;

1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-1H-indoles-6-formic acid methyl ester;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(7-nitroindoline-1-yl) propan-2-ol;

1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-1H-indoles-4-nitrile;

3-(5-benzyloxy indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-1H-indoles-5-nitrile;

3-(3-dimethylaminomethyl-5-methoxyl group indoles-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(5-methoxyl group-2 methyl indole-1-yl) propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2 methyl indole-1-yl) propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(3-skatole-1-yl) propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(7-skatole-1-yl) propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(5-nitroindoline-1-yl) propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2-phenylindone-1-yl) propan-2-ol;

(2-phenyl-1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-the 1H-indol-3-yl) acetonitrile;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-pyrrolo-[2,3-c] pyridine-1-base propan-2-ol;

3-(7-ethylindole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

3-(2,3-dimethyl-5-nitroindoline-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(6-trifluoro methyl indole-1-yl) propan-2-ol;

1,1,1-three fluoro-3-(7-fluoro indole-1-yl)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-the 1H-indole-6-carbonitrile;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-indoles-1-base propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-pyrrolo-[2,3-b] pyridine-1-base propan-2-ol;

1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-1H-indole-2-carboxylic acid ethyl ester;

3-(2,3-dimethyl indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-1H-indoles-3-nitrile;

1-(1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-the 1H-indol-3-yl) ethyl ketone;

3-(3-dimethylaminomethyl indoles-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

(1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-the 1H-indol-3-yl) the acetate ethyl ester;

2-(1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-the 1H-indol-3-yl) ethanamide;

3-(5-bromo indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-3-(5-fluoro indole-1-yl)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

3-(5-chloro-indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(5-methoxyl group indoles-1-yl) propan-2-ol;

3-(5,6-dimethoxy indoles-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(4-nitroindoline-1-yl) propan-2-ol; And

The 5-methyl isophthalic acid-3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-1H-indole-2-carboxylic acid ethyl ester,

Or its tautomer, prodrug, solvate or salt.

The compound of preferred formula (IA) comprises following compound:

1-biphenyl-3-base-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(3-chloro-phenyl-)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-naphthalene-1-base-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(3-fluorophenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(4-fluorophenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(4-chloro-phenyl-)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl)-1-quinolyl-4 ethanol;

2,2,2-three fluoro-1-(1H-indoles-4-yl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1,1,1-three fluoro-3-phenyl-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl)-1-quinolyl-4 ethanol;

2,2,2-three fluoro-1-isoquinolyl-1-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(3-aminophenyl)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-naphthalene-1-base-1-(1-phenyl-1H-indoles-5-yl) ethanol;

2,2,2-three fluoro-1-phenyl-1-(1-pyridine-2-base-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-phenyl-1-(1-p-tolyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-phenyl-1-(1-o-tolyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-naphthalene-1-base-1-(1-o-tolyl-1H-indazole-5-yl) ethanol;

3-[2,2,2-three fluoro-1-hydroxyl-1-(1-phenyl-1H-indazole-5-yl) ethyl] phenol;

4-[2,2,2-three fluoro-1-hydroxyl-1-(1-phenyl-1H-indazole-5-yl) ethyl] phenol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-o-tolyloxy propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-m-tolyloxy propan-2-ol;

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-p-tolyloxy propan-2-ol;

3-(3, the 5-dichlorophenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-base 1 propan-2-ol;

6-methyl-2-[3,3,3-three fluoro-2-hydroxyl-2-(1-phenyl-1H-indazole-5-yl) rosickyite base]-4-trifluoromethyl nicotine nitrile;

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(4-nitroindoline-1-yl) propan-2-ol;

Or its tautomer, prodrug, solvate or salt.

The present invention also provides the method for a kind of preparation formula (IA) compound

Wherein: C is CH ₂, D is CR ⁴R ⁵(R wherein ⁴Be CF ₃, and R ⁵Be OH), E is a chemical bond, and A, B, R ¹, R ²And R ³All definition as mentioned, this method comprises:

(a) make formula (II) nitrile and suitable reductive agent, for example hydrogenation di-isopropyl aluminium for example reacts in the methylene dichloride at appropriate solvent, so that formula (III) aldehyde to be provided

(b) make formula (III) aldehyde and [1,3] dithian-2-base trimethyl silyl (IV), exist down in suitable alkali, for example just-butyllithium, for example react among the THF at appropriate solvent, so that formula V thioketene acetal (thioketene acetal) to be provided

(c) make formula V thioketene acetal and triethyl-silicane, exist down in acid, for example TFA for example reacts in the methylene dichloride at solvent, and gets formula (VI) sulfo-ketal

(d) make formula (VI) sulfo-ketal and methyl iodide, for example react in the acetonitrile, so that formula (VII) aldehyde to be provided at solvent

(e) make formula (VII) aldehyde and (trifluoromethyl) trimethyl silyl, exist in suitable fluorine source down, for example tetrabutylammonium is for example reacted among the THF at appropriate solvent, so that formula (VIII) alcohol to be provided

(f) make formula (VIII) alcohol, exist down, in for example oxidation in the methylene dichloride of appropriate solvent, to form formula (IX) ketone in Dess-Martin periodinane

(g) make formula (IX) ketone and organometallic reagent R ³M, the refined reagent of Green for example, wherein M is MgBr, MgCl or MgI, or and organolithium reagent, wherein M is Li, for example reacts among ether or the THF at appropriate solvent, to form formula (IA) compound

Perhaps, formula (IA) compound, wherein C is a chemical bond, and A, B, D, E, R ¹, R ², and R ³All definition as mentioned can be via from formula (III) aldehyde, and according to step (e), (f) and (g) make.

The present invention also provides the method for preparation formula (IA) compound, wherein R ³Be NR ⁶R ⁷, OR ⁸Or SR ⁹, C is CH ₂, D is CR ⁴R ⁵(R wherein ⁴Be CF ₃, and R ⁵Be OH), E is CH ₂, and A, B, R ¹And R ²All definition as mentioned, this method comprises:

(a ') make formula (IX) ketone and formula (XI) sulphur ylide compound, exist down in suitable alkali, for example sodium hydride for example reacts among the THF at appropriate solvent, so that formula (XII) epoxide to be provided

(b ') makes formula (XII) epoxide and formula (XIII) compound R ³H randomly exists down in alkali, and for example sodium hydride for example reacts among the DMF at appropriate solvent, so that formula (IA) compound to be provided.Perhaps, formula (IA) compound, wherein C is a chemical bond, and A, B, D, E, R ¹, R ²And R ³All definition as mentioned can be via from formula (III) aldehyde, and make according to step (e), (f), (a ') and (b ')

Perhaps, formula (IA) compound, wherein C is CH ₂, D is CR ⁴R ⁵(R wherein ⁴Be CF ₃, and R ⁵Be OH), and E is chemical bond, can use following method to make via from formula (VII) aldehyde:

(a ") makes formula (VII) aldehyde and formula (X) organometallic reagent R ³M, for example refined reagent of Green (M is MgBr, MgCl or MgI), or organolithium reagent (M is Li) for example reacts among ether or the THF at appropriate solvent, to form formula (XIV) alcohol

(b ") makes formula (XIV) alcohol and Dess Martin periodinane reagent, in for example oxidation among methylene dichloride or the THF of appropriate solvent, so that formula (XV) ketone to be provided

(c ") make formula (XV) ketone and (trifluoromethyl) trimethyl silyl, exist in suitable fluorine source down, for example tetrabutylammonium is for example reacted among the THF at appropriate solvent, so that formula (IA) compound to be provided.Perhaps, formula (IA) compound, wherein C is a chemical bond, and A, B, D, E, R ¹, R ²And R ³All definition as mentioned can be via from formula (III) aldehyde, and make according to step (a "), (b ") and (c ")

The invention still further relates to formula (IB) compound

Wherein:

R ¹Be aryl, heteroaryl or C ₃-C ₇Cycloalkyl, each group are randomly independent to be replaced by one to three substituting group, and described substituting group is selected from C ₁-C ₃Alkyl, hydroxyl, halogen, oxo, methoxyl group, amino, wherein nitrogen-atoms is randomly independent of methyl list-or two replace, or methylthio group wherein sulphur atom randomly be oxidized to sulfoxide or sulfone;

R ²Be hydrogen or halogen;

A and B independently are CH or N separately;

C and E independently be separately chemical bond or-CH ₂-;

D is CR ⁴R ⁵-, wherein:

R ⁴Be C ₁-C ₈Alkyl, C ₂-C ₈Thiazolinyl, C ₂-C ₈Alkynyl, carbocyclic ring, heterocyclic radical, aryl, heteroaryl, carbocyclic ring-C ₁-C ₈Alkyl, aryl-C ₁-C ₈Alkyl, aryl-C ₁-C ₈Haloalkyl, heterocyclic radical-C ₁-C ₈Alkyl, heteroaryl-C ₁-C ₈Alkyl, carbocyclic ring-C ₂-C ₈Thiazolinyl, aryl-C ₂-C ₈Thiazolinyl, heterocyclic radical-C ₂-C ₈Thiazolinyl or heteroaryl-C ₂-C ₈Thiazolinyl, each group are randomly independent to be replaced by one to three substituting group,

R wherein ⁴Each substituting group be C independently ₁-C ₃Alkyl, C ₂-C ₃Thiazolinyl, C ₂-C ₃Alkynyl, C ₁-C ₃Alkoxyl group, aminocarboxyl, C ₁-C ₃Alkyl amino-carbonyl, C ₁-C ₃Dialkyl amino carbonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro or C ₁-C ₃Alkylthio, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone, wherein R ⁴Can not be trifluoromethyl, R ⁵For-OH;

R wherein ³Each substituting group be aryl, heteroaryl, heterocyclic radical, C independently ₁-C ₅Alkyl, C ₁-C ₅Thiazolinyl, cycloalkyl, cycloalkenyl group, acyl group, carbalkoxy, C ₁-C ₅Alkanoyloxy, C ₁-C ₅Alkyloyl, aroyl, C ₁-C ₅Alkyl amide, alkyl amino-carbonyl, dialkyl amino carbonyl, aminocarboxyl oxygen base, C ₁-C ₅Alkyl amino carbonyl oxy, C ₁-C ₅Dialkyl amino carbonyl oxy, C ₁-C ₅Alkyl amide, C ₁-C ₅Alkoxycarbonyl amido, C ₁-C ₅Alkyl sulfonyl-amino, amino-sulfonyl, C ₁-C ₅Alkyl amino sulfonyl, C ₁-C ₅Dialkyl amino sulfonyl, C ₁-C ₅Alkoxyl group, aryloxy, halogen, hydroxyl, oxo, cyano group, trifluoromethyl, nitro, carboxyl, aminocarboxyl, amino, wherein nitrogen-atoms is randomly independent of C ₁-C ₅The alkyl list-or two replacements, or C ₁-C ₅Alkylthio wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,

R wherein ³Each substituting group randomly independently replaced by one to three substituting group, described substituting group is selected from aryl, heteroaryl, heterocyclic radical, acyl group, C ₁-C ₅Alkyl, C ₁-C ₅Alkanoyloxy, C ₁-C ₅Alkyloyl, C ₁-C ₅Alkyl amide, alkyl amino-carbonyl, dialkyl amino carbonyl, C ₁-C ₅Alkyl sulfonyl-amino, amino-sulfonyl, C ₁-C ₅Alkyl amino sulfonyl, C ₁-C ₅Dialkyl amino sulfonyl, C ₁-C ₅Alkoxyl group, aryloxy, halogen, hydroxyl, oxo, cyano group, trifluoromethyl, nitro, aminocarboxyl, amino, wherein nitrogen-atoms is randomly independent of C ₁-C ₅The alkyl list-or two replacements, C ₁-C ₅Cycloalkyl or C ₁-C ₅Alkylthio wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,

R wherein ⁶Be hydrogen or C ₁-C ₃Alkyl, and

R wherein ⁷, R ⁸And R ⁹Each substituting group randomly independently replaced by one to three substituting group, described substituting group is selected from heteroaryl, heterocyclic radical, acyl group, C ₁-C ₅Alkyl, C ₁-C ₅Alkyl amide, alkyl amino-carbonyl, dialkyl amino carbonyl, C ₁-C ₅Alkyl sulfonyl-amino, amino-sulfonyl, C ₁-C ₅Alkyl amino sulfonyl, C ₁-C ₅Dialkyl amino sulfonyl, C ₁-C ₅Alkoxyl group, aryloxy, halogen, hydroxyl, oxo, cyano group, trifluoromethyl, nitro, aminocarboxyl, amino, wherein nitrogen-atoms is randomly independent of C ₁-C ₅The alkyl list-or two replacements, or C ₁-C ₅Alkylthio wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,

Or its tautomer, prodrug, solvate or salt.

An aspect of of the present present invention comprises formula (IB) compound, wherein:

R ¹Be aryl or heteroaryl, each group is randomly replaced by one to three substituting group, and described substituting group is selected from hydroxyl, halogen or oxo;

R ²Be hydrogen;

C is a chemical bond;

E be chemical bond or-CH ₂-; And

D is-CR ⁴R ⁵-, wherein:

R ⁴Be C ₁-C ₅Alkyl, C ₂-C ₅Thiazolinyl, C ₃-C ₆Cycloalkyl, phenyl, C ₃-C ₆Cycloalkyl-C ₁-C ₃Alkyl, phenyl-C ₁-C ₃Alkyl, phenyl-C ₁-C ₃Haloalkyl, C ₃-C ₆Cycloalkyl-C ₂-C ₃Thiazolinyl, phenyl-C ₂-C ₃Thiazolinyl, each group are randomly independent to be replaced by one to three substituting group,

R wherein ⁴Each substituting group be C independently ₁-C ₃Alkyl, C ₂-C ₃Thiazolinyl, C ₂-C ₃Alkynyl, C ₁-C ₃Alkoxyl group, aminocarboxyl, C ₁-C ₃Alkyl amino-carbonyl, C ₁-C ₃Dialkyl amino carbonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro or C ₁-C ₃Alkylthio,

Wherein sulphur atom randomly is oxidized to sulfoxide or sulfone, wherein R ⁴Can not be trifluoromethyl, and

R ⁵For-OH,

Or its tautomer, prodrug, solvate or salt.

R ¹Be phenyl, randomly replaced by one to three halogen group;

A is N;

B is CH;

D is-CR ⁴R ⁵-, wherein:

R ⁴Be C ₁-C ₅Alkyl, C ₃-C ₆Cycloalkyl, C ₃-C ₆Cycloalkyl-methyl-or benzyl, each group is randomly independent to be replaced by one to three substituting group,

R wherein ⁴Each substituting group be methyl, methoxyl group, fluorine, chlorine, bromine, cyano group, trifluoromethyl or hydroxyl, wherein R independently ⁴Can not be trifluoromethyl, and

R ⁵For-OH; And

Piperazine, 1,2,3,4-tetrahydroisoquinoline or N-ethyl-N '-methylbenzene-1,2-diamines, 1,2,3,4-tetrahydroquinoline, NR ⁶R ⁷, OR ⁸Or SR ⁹Each group is randomly independent to be replaced by one to three substituting group,

R wherein ⁶Be hydrogen or methyl, and

R wherein ⁷, R ⁸And R ⁹Each substituting group be heterocyclic radical, C independently ₁-C ₅Alkyl, cycloalkyl, acyl group, C ₁-C ₅Alkoxyl group, halogen, hydroxyl, oxo, cyano group, trifluoromethyl, aminocarboxyl, amino, wherein nitrogen-atoms is randomly independent of C ₁-C ₅The alkyl list-or two replacements,

Or C ₁-C ₅Alkylthio wherein sulphur atom randomly is oxidized to sulfoxide or sulfone, or its tautomer, prodrug, solvate or salt.

The one side of above-mentioned specific embodiments comprises formula (IB) compound, wherein:

Piperazine, 1,2,3,4-tetrahydroisoquinoline or N-ethyl-N '-methylbenzene-1,2-diamines, 1,2,3, the 4-tetrahydroquinoline,

R wherein ³Each substituting group be C independently ₁-C ₅Alkyl, acyl group, C ₁-C ₅Alkoxyl group, halogen, hydroxyl, oxo, cyano group, trifluoromethyl, aminocarboxyl, amino, wherein nitrogen-atoms is randomly independent of C ₁-C ₅The alkyl list-or two replacements, C ₁-C ₅Thiazolinyl, carboxyl or C ₁-C ₅Alkylthio wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,

R wherein ³Each substituting group randomly independently replaced by one to three substituting group, described substituting group is selected from heterocyclic radical, C ₁-C ₅Alkyl, halogen, hydroxyl, oxo, cyano group, trifluoromethyl, aminocarboxyl, amino, wherein nitrogen-atoms is randomly independent of C ₁-C ₅The alkyl list-or two replacements, or C ₁-C ₅Alkylthio wherein sulphur atom randomly is oxidized to sulfoxide or sulfone, or its tautomer, prodrug, solvate or salt.

The representative compounds of the formula according to the present invention (IB) is to enclose with literary composition with Table I B, and its intermediate hurdles A is the compound title according to standardized denomination, and hurdle B is its corresponding chemical structure.

Preferred formula (IB) compound comprises following:

Cyclopropyl phenyl-(1-phenyl-1H-indazole-5-yl) methyl alcohol;

Cyclopropyl-(3, the 5-dichlorophenyl)-(1-phenyl-1H-indazole-5-yl) methyl alcohol;

1-cyclopropyl-2-phenyl-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-cyclopropyl-2-(3, the 5-dichlorophenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-cyclopropyl-1-(1-phenyl-1H-indazole-5-yl)-2-p-tolyl ethanol;

1-cyclopropyl-1-(1-phenyl-1H-indazole-5-yl)-2-m-tolyl ethanol;

Cyclopropyl phenyl-(1-phenyl-1H-benzotriazole-5-yl) methyl alcohol;

Cyclopropyl-[1-(4-fluorophenyl)-1H-benzotriazole-5-yl] phenyl methanol;

1-(1-phenyl-1H-indazole-5-yl)-1-quinolyl-4 ethanol;

1-(1-phenyl-1H-indazole-5-yl)-1-quinolyl-4 third-1-alcohol;

1-(4-fluoronaphthalene-1-yl)-1-(1-phenyl-1H-H-azoles-5-yl) third-1-alcohol;

1-(1-allyl group-1H-indol-3-yl)-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-methyl-prop-1-alcohol; And

1-(1-allyl group-1H-indol-3-yl)-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] third-1-alcohol, or its tautomer, prodrug, solvate or salt.

The present invention also provides the method for preparation formula (IB) compound

Wherein: A, B, C, D, E, R ¹, R ²And R ³All definition as mentioned, this method comprises:

(a) make formula (II) nitrile and (XVI) organometallic reagent R ⁴-M, the refined reagent of Green (M is MgBr, MgCl or MgI) for example for example reacts in THF or the ether at appropriate solvent, with acquisition formula (XVII) ketone

(b) make formula (XVII) ketone and formula (X) organometallic reagent R ³M, for example refined reagent of Green (M is MgBr, MgCl or MgI), or organolithium reagent (M is Li) for example reacts among ether or the THF at appropriate solvent, so that formula (IB) compound to be provided

Perhaps, formula (IB) compound, wherein C is chemical bond or CH ₂, D is CR ⁴R ⁵(R wherein ⁵Be OH), reaching E is chemical bond, and A, B, R ¹, R ², R ³And R ⁴All definition as mentioned, it can use the following step to make via from formula (XV) ketone:

(a ') makes formula (XV) ketone and formula (XVI) organometallic reagent R ⁴M, for example refined reagent of Green (M is MgBr, MgCl or MgI), or organolithium reagent (M is Li) for example reacts among ether or the THF at appropriate solvent, so that formula (IB) compound to be provided

Perhaps, formula (IB) compound, wherein R ³Be NR ⁶R ⁷, OR ⁸Or SR ⁹, C is chemical bond or CH ₂, D is CR ⁴R ⁵(R wherein ⁵Be OH), and E is CH ₂, and A, B, R ¹, R ²And R ⁴All as mentioned the definition, can via from formula (III) or (VII) aldehyde begin and make:

(a ") makes formula (III) or (VII) aldehyde and formula (XVI) organometallic reagent R ⁴M, for example refined reagent of Green (M is MgBr, MgCl or MgI), or organolithium reagent (M is Li) for example reacts in THF or the ether at appropriate solvent, with acquisition formula (XVIII) alcohol

(b ") makes formula (XVIII) alcohol, exists down in Dess-Martin periodinane, in for example oxidation in the methylene dichloride of appropriate solvent, to form formula (XV) ketone

(c ") make formula (XIX) ketone and formula (XI) sulphur ylide compound, exist down in suitable alkali, for example sodium hydride for example reacts among the THF at appropriate solvent, so that formula (XX) epoxide to be provided

(d ") makes formula (XX) epoxide and formula (XIII) compound R ³No matter H is not use or use alkali, and for example sodium hydride for example reacts among the DMF at appropriate solvent, so that formula (IB) compound to be provided

In another aspect of this invention, compound according to the present invention is deployed into pharmaceutical composition, and it comprises significant quantity, preferably the The compounds of this invention of significant quantity pharmaceutically, or its tautomer, prodrug, solvate or salt, and pharmaceutically acceptable vehicle or carrier.

The present invention also provides a kind of method of regulating glucocorticoid receptor function in the patient, this method comprise to this patient's effective dosage according to The compounds of this invention, or its tautomer, prodrug, solvate or salt.

The present invention further provides a kind of method of in the patient of this treatment of needs, treating by glucocorticoid receptor function disease states mediated or symptom, this method comprises the pharmaceutically useful The compounds of this invention to this patient's effective dosage, or its tautomer, prodrug, solvate or salt.

In addition, the present invention also provides a kind of method for the treatment of morbid state or symptom in the patient of this treatment of needs, this morbid state or symptom are selected from: type ii diabetes, obesity, cardiovascular disorder, hypertension, arteriosclerosis, neurological disease, suprarenal gland and pituitary tumor and glaucoma, this method comprises the pharmaceutically useful The compounds of this invention to this patient's effective dosage, or its tautomer, prodrug, solvate or salt.

The invention provides a kind of method of in the patient of this treatment of needs, treating the disease that it is characterized by inflammatory, supersensitivity or hyperplasia process, this method comprises the pharmaceutically useful The compounds of this invention to this patient's effective dosage, or its tautomer, prodrug, solvate or salt.In embodiment preferred of the present invention, it is characterized by the disease of inflammatory, supersensitivity or hyperplasia process, be selected from:(i) tuberculosis; (ii) serious shock state (xviii) alternative medicine of disease (xii) neurological disease (xiii) hematologic disease (xiv) tumor disease (xv) endocrine system disease (xvi) organ in rheumatoid disease or autoimmune disease or joint disease (iii) anaphylactia (iv) vasculitis disease (v) skin disease (vi) ephrosis (vii) hepatopathy (viii) gastrointestinal disease (ix) proctology disease (x) disease of eye (xi) ear, nose and larynx (ENT) zone and tissue transplantation and graft-vs.-host disease (xvii); Reach (xix) pain of inflammatory origin.In another embodiment preferred of the present invention, it is characterized by inflammatory, the disease of supersensitivity or hyperplasia process is selected from:type i diabetes, osteoarthritis, Guillain-Barre syndrome, restenosis after the percutaneous tranluminal coronary angioplasty, alzheimer's disease, acute and chronic pain, atherosclerosis, reperfusion injury, bone resorption disease, congestive heart failure, myocardial infarction, thermal damage, the multiple organ injury of wound secondary, acute purulent meningitis, necrotizing enterocolitis and and hemodialysis, leucopheresis and the relevant syndrome of granulocyte blood transfusion.

The present invention further provides the method for in the patient of this treatment of needs, treating above mentioned morbid state or symptom, these methods comprise in succession or simultaneously to this patient's administration: (a) the pharmaceutically useful The compounds of this invention of significant quantity, or its tautomer, prodrug, solvate or salt; With (b) pharmaceutically acceptable glucocorticosteroid.

The present invention further provides a kind of method that detects glucocorticoid receptor function in sample, it comprises: (a) make contacting according to The compounds of this invention or its tautomer, prodrug, solvate or salt of sample and selected amount; Detect the amount that in sample, combines glucocorticoid receptor with (b) according to The compounds of this invention or its tautomer, prodrug, solvate or salt.In embodiment preferred of the present invention, according to compound of the present invention or its tautomer, prodrug, solvate or salt is that this marker is selected from detectable marker mark: radio-labeling, fluorescence labels, chemoluminescence label, chromophoric group and spin labeling.

The present invention also provides a kind of glucocorticoid receptor distribution imaging method that makes in sample or patient, this method comprises: (a) make sample contact or to patient's administration have detectable according to The compounds of this invention or its tautomer, prodrug, solvate or salt; (b) in sample or patient, use imaging device, detect spatial distribution and the amount that have detectable and be bonded to glucocorticoid receptor, to obtain image according to The compounds of this invention or its tautomer, prodrug, solvate or salt; And (c) in sample, show have detectable and be bonded to glucocorticoid receptor according to the spatial distribution of The compounds of this invention or its tautomer, prodrug, solvate or salt and the image of amount.In embodiment preferred of the present invention, imaging device is selected from: radioscintigraphy (art),, Magnetic resonance imaging (MRI), computer (x line) tomography (CT scan) or positron emission tomography (PET).

The present invention also provides a kind of in vitro test kit of diagnostic assay glucocorticoid receptor function that supplies in sample, it comprises: (a) The compounds of this invention of significant quantity is gone up in diagnosis, or its tautomer, prodrug, solvate or salt; Working instructions with (b) diagnostic kit.

The definition of the term that uses and usage

The term that does not clearly define should be given those meanings that those of ordinary skill in the art is given after understanding disclosure and context herein.But, unless opposite appointment is arranged, in being used in patent specification and the appended claim with literary composition the time, following term is to have indicated meaning, and meets following usage.

A. chemical nomenclature, term and usage

In defined hereinafter group, atomic group or the part group, carbonatoms often is specified in and is next to before the group, for example C ₁-C ₁₀Alkyl refers to have the alkyl or the group of 1 to 10 carbon atom.Be applied to " rudimentary " term of any carbon-containing group, refer to contain the group of 1 to 8 carbon atom, by suitable mode (being that cyclic group must have at least 3 atoms to constitute ring) this group.Generally speaking, for the group that comprises two or more subunits group, the group of Zhi Chenging is to be the group tie point at last, for example " alkylaryl " refers to formula Alk-Ar-monoradical, yet " aralkyl " refers to formula Ar-Alk monoradical (wherein Alk is an alkyl, and Ar is an aryl).In addition, censure the use of the term of monoradical, in divalent group is suitable situation, will be interpreted as censuring indivedual divalent groups, on the contrary and it is also right.Unless otherwise, otherwise the definition of term control and the routine of conventional stationary atom valency, in all chemical formulas and group, supposed and realized.

" alkyl " or " groups " term refers to side chain or straight chain saturated aliphatic hydrocarbon monoradical.This term is to be example with the following groups, for example methyl, ethyl, just-propyl group, 1-methylethyl (sec.-propyl), just-butyl, just-amyl group, 1,1-dimethyl ethyl (tertiary butyl) etc.It can be abbreviated as " Alk ".

" thiazolinyl " or " thiazolinyl group " term refers to contain the side chain or the linear aliphatic hydrocarbon monoradical of at least one carbon-to-carbon double bond.This term is to be example with the following groups, for example vinyl, propenyl, just-butenyl, isobutenyl, 3-methyl but-2-ene base, just-pentenyl, heptenyl, octenyl, decene base etc.

" alkynyl " or " ethynylene group " term refers to contain the side chain or the linear aliphatic hydrocarbon monoradical of at least one carbon-to-carbon three key.This term is to be example with the following groups, for example ethynyl, proyl, just-butynyl, 2-butyne base, 3-methyl butynyl, just-pentynyl, heptyne base, octyne base, decynyl etc.

" alkylidene group " or " alkylene group " term refers to have the side chain or the straight chain saturated aliphatic hydrocarbon divalent group of specified carbonatoms.This term is to be example with the following groups, for example methylene radical, ethylidene, propylidene, just-butylidene etc., and alternately and considerably in be expressed as herein-(alkyl)-.

" alkenylene " or " alkenylene group " term refers to have the side chain or the linear aliphatic hydrocarbon divalent group of specified carbonatoms and at least one carbon-to-carbon double bond.This term is to be example with the following groups, for example vinylidene, propenylidene, just-crotonylidene etc., and alternately and considerably in be expressed as herein-(thiazolinyl)-.

" alkynylene " or " alkynylene group " term refers to contain the side chain or the linear aliphatic hydrocarbon divalent group of at least one carbon-to-carbon three key.This term is to be example with the following groups, for example ethynylene, inferior proyl, just-butynelene, 2-butynelene, 3-methyl butynelene, just-Ya pentynyl, inferior heptyne base, inferior octyne base, inferior decynyl etc., and alternately and considerably in be expressed as herein-(alkynyl)-.

" alkoxyl group " or " alkoxy grp " term refers to formula AlkO-monoradical, and wherein Alk is an alkyl.This term is to be example with the following groups, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, sec-butoxy, tert.-butoxy, pentyloxy etc.

" aryloxy ", " aryloxy group " term refer to formula ArO-monoradical, and wherein Ar is an aryl.This term is to be example, for example phenoxy group, naphthyloxy etc. with the following groups.

" alkyl-carbonyl ", " alkyl oxycarbonyl group ", " alkyloyl " or " alkanol groups " term refer to formula AlkC (O)-monoradical, and wherein Alk is alkyl or hydrogen.

" aryl carbonyl ", " aryl carbonyl group ", " aroyl " or " aroyl group " term refer to formula ArC (O)-monoradical, and wherein Ar is an aryl.

" acyl group " or " acyl group group " term refers to formula RC (O)-monoradical, and wherein R is the substituting group that is selected from hydrogen or organic substituent.Substituting group for example comprises alkyl, aryl, aralkyl, cycloalkyl, heterocyclic radical, heteroaryl, heteroaralkyl etc.Therefore, this term comprises alkyl-carbonyl and aryl carbonyl.

" amide group " or " acyl amino " term refers to formula RC (O) N (R)-monoradical, and wherein each R is the substituting group that is selected from hydrogen or substituted radical.

" carbalkoxy " or " carbalkoxy group " term refers to formula AlkO-C (O)-monoradical, and wherein Alk is an alkyl.Carbalkoxy for example comprises methoxycarbonyl, ethoxycarbonyl, tertbutyloxycarbonyl etc.

" aryloxycarbonyl " or " aryloxycarbonyl group " term refers to formula ArO-C (O)-monoradical, and wherein Ar is an aryl.

" alkyl-carbonyl oxygen base " or " alkyl-carbonyl oxygen groups " or " alkanoyloxy " or " alkyloyloxyethyl group " term refer to formula AlkC (O) O-monoradical, and wherein Alk is an alkyl.

" aryl carbonyl oxygen base " or " aryl carbonyl oxygen groups " or " aroyl oxygen base " or " aroyl oxygen groups " term refer to formula ArC (O) O-monoradical, and wherein Ar is an aryl.

" alkyl amino carbonyl oxy " or " alkyl amino carbonyl oxy group " term refers to formula R ₂NC (O) O-monoradical, wherein each R independently is hydrogen or low alkyl group.

" alkoxycarbonyl amido " or " alkoxycarbonyl ammonia group " term refers to formula ROC (O) NH-monoradical, and wherein R is a low alkyl group.

" alkyl-carbonyl-amino " or " alkyl-carbonyl-amino group " or " alkyl amide " or " alkyl amide group " term refer to formula AlkC (O) NH-monoradical, and wherein Alk is an alkyl.Alkyl-carbonyl-amino for example comprises acetamido (CH ₃C (O) NH-).

" alkyl amino carbonyl oxy " or " alkyl amino carbonyl oxy group " term refers to formula AlkNHC (O) O-monoradical, and wherein Alk is an alkyl.

" amino " or " amine groups " term refers to-NH ₂Group.

" alkylamino " or " alkylamino group " term refers to formula (Alk) NH-monoradical, and wherein Alk is an alkyl.Alkylamino for example comprises methyl amido, ethyl amido, propyl group amido, butyl amino, tertiary butyl amino etc.

" dialkyl amido " or " dialkyl amino group " term refers to (Alk) N-monoradical of formula (Alk), and wherein each Alk is alkyl independently.Dialkyl amido for example comprises dimethyl amido, methyl ethyl-amine base, diethyl amido, dipropyl amino, ethyl Propylamino etc.

" substituted amino " or " substituted amine groups " term refers to formula-NR ₂Monoradical, wherein each R is independently for being selected from the substituting group of hydrogen or specific substituting group (but wherein two R are not hydrogen).Substituting group for example comprises alkyl, alkyloyl, aryl, aralkyl, cycloalkyl, heterocyclic radical, heteroaryl, heteroaralkyl etc.

" alkoxycarbonyl amido " or " alkoxycarbonyl ammonia group " term refers to formula AlkOC (O) NH-monoradical, and wherein Alk is an alkyl.

" urea groups " or " urea groups " term refers to formula R ₂NC (O) NH-monoradical, wherein each R is hydrogen or alkyl independently.

" halogen " or " halogen group " term refers to fluorine, chlorine, bromine or iodine.

" halo " refers to that one or more hydrogen atom of group is replaced by halogen group.

" haloalkyl " or " haloalkane group " term refers to side chain or straight chain saturated aliphatic hydrocarbon monoradical, and wherein one or more hydrogen atom is independent is separately replaced by halogen atom.This term is to be example with the following groups, chloromethyl, 1 for example, 2-two bromotrifluoromethanes, 1,1,1-trifluoro propyl, 2-iodine butyl, 1-chloro-2-bromo-3-fluorine amyl group etc.

" sulfenyl ", " methylthio group ", " thioether " or " sulfide group " term refer to formula-S-divalent group.

" alkylthio " or " alkylthio group " term refers to formula AlkS-monoradical, and wherein Alk is an alkyl.Group for example comprise methylthio group, ethylmercapto group, just-propyl group sulfenyl, iprotiazem base, just-butylthio etc.

" arylthio " or " artyl sulfo " term refers to formula ArS-monoradical, and wherein Ar is an aryl.

" sulfinyl ", " sulfinyl group ", " sulfinyl " or " thionyl group " term refer to formula-SO-divalent group.

" alkylsulfonyl " or " sulfonyl group " term refers to formula-SO ₂-divalent group.

" sulfuryl amino " or " Herbicidal sulphonylamino group " term refers to formula-SO ₂The NR-divalent group, wherein R is hydrogen or substituting group.

" amido alkylsulfonyl " or " amido sulfonyl group " term refers to formula NR ₂SO ₂-monoradical, wherein R independently is hydrogen or substituting group separately.

" carbocyclic ring " or " carbocyclic ring family group " term, 3-to the 15-unit's monocycle shape or polycyclic unit price or the divalent group that refer to stable aliphatic series, only be made up of carbon and hydrogen atom, it can comprise one or more through condensing or the ring of bridge joint, preferably 5-to 7-unit's monocycle shape or 7-to 10 Yuan double-ring ring.Unless otherwise, otherwise carbocyclic ring can connect at any carbon atom place that meeting obtain stable structure, and if be substituted, and then can be substituted at any suitable carbon atom place that meeting obtains stable structure.This term comprises cycloalkyl (comprising spiro cycloalkyl group), cycloalkylidene, cycloalkenyl group, inferior cycloalkenyl group, cycloalkynyl radical and inferior cycloalkynyl radical etc.

" cycloalkyl " or " naphthene group " term, saturated 3-to the 15-unit's monocycle shape or the polycyclic monoradical that refer to stable aliphatic series, only be made up of carbon and hydrogen atom, it can comprise one or more through condensing or the ring of bridge joint, preferably 5-to 7-unit's monocycle shape or 7-to 10-unit double-ring ring.Unless otherwise, otherwise cycloalkyl ring can connect at any carbon atom place that meeting obtain stable structure, and if be substituted, and then can be substituted at any suitable carbon atom place that meeting obtains stable structure.Cycloalkyl for example comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, ring decyl, norborneol alkyl, adamantyl, tetralyl (naphthane), 1-decahydro naphthyl, dicyclo [2.2.2] octyl, 1-methyl cyclopropyl, 2-methylcyclopentyl, 2-methyl ring octyl group etc.

" cycloalkenyl group " or " cyclene group " term, 5-to the 15-unit's monocycle shape or the polycyclic monoradical that refer to stable aliphatic series, has at least one carbon-to-carbon double bond, and only form by carbon and hydrogen atom, it can comprise one or more through condensing or the ring of bridge joint, preferably 5-to 7-unit's monocycle shape or 7-to 10-unit double-ring ring.Unless otherwise, otherwise the cyclenes basic ring can connect at any carbon atom place that meeting obtain stable structure, and if be substituted, and then can be substituted at any suitable carbon atom place that meeting obtains stable structure.Cycloalkenyl group for example comprises cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctene base, cyclonoene base, cyclodecene base, norbornene, 2-methyl cyclopentene base, 2-methyl cyclooctene base etc.

" cycloalkynyl radical " or " cycloalkyne group " term, 8-to the 15-unit's monocycle shape or the polycyclic monoradical that refer to stable aliphatic series, has at least one carbon-to-carbon three key, and only form by carbon and hydrogen atom, it can comprise one or more through condensing or the ring of bridge joint, preferably 8-to 10-unit's monocycle shape or 12-to 15-unit double-ring ring.Unless otherwise, otherwise the cycloalkyne basic ring can connect at any carbon atom place that meeting obtain stable structure, and if be substituted, and then can be substituted at any suitable carbon atom place that meeting obtains stable structure.Cycloalkynyl radical for example comprises cyclooctyne base, cyclonoyne base, cyclodecyne base, 2-methyl cyclooctyne base etc.

" cycloalkylidene " or " cycloalkylidene group " term, refer to stablize radical of saturated aliphatic 3-to 15-unit's monocycle shape or polycyclic divalent group, only be made up of carbon and hydrogen atom, it can comprise one or more through condensing or the ring of bridge joint, preferably 5-to 7-unit's monocycle shape or 7-to 10-unit double-ring ring.Unless otherwise, otherwise cycloalkyl ring can connect at any carbon atom place that meeting obtain stable structure, and if be substituted, and then can be substituted at any suitable carbon atom place that meeting obtains stable structure.Cycloalkylidene for example comprises cyclopentylidene etc.

" inferior cycloalkenyl group " or " inferior cyclene group " term, 5-to the 15-unit's monocycle shape or the polycyclic divalent group that refer to stable aliphatic series, has at least one carbon-to-carbon double bond, and only form by carbon and hydrogen atom, it can comprise one or more through condensing or the ring of bridge joint, preferably 5-to 7-unit's monocycle shape or 7-to 10-unit double-ring ring.Unless otherwise, otherwise inferior cycloalkenyl group ring can connect at any carbon atom place that meeting obtain stable structure, and if be substituted, and then can be substituted at any suitable carbon atom place that meeting obtains stable structure.Inferior cycloalkenyl group for example comprises time cyclopentenyl, cyclohexenyl, inferior cycloheptenyl, inferior cyclooctene base, inferior cyclonoene base, inferior cyclodecene base, inferior norbornene, 2-methyl cyclopentenylidene, the inferior cyclooctene base of 2-methyl etc.

" aryl " or " aryl group " term refers to the aromatic carbocyclic shape unit price or the divalent group of 6 to 14 carbon atoms to have monocycle (for example phenyl or phenylene) or multiple condensed ring (for example naphthyl or anthryl).Unless otherwise, otherwise aryl rings can connect at any suitable carbon atom place that meeting obtain stable structure, and if be substituted, and then can be substituted at any suitable carbon atom place that meeting obtains stable structure.Aryl for example comprises phenyl, naphthyl, anthryl, phenanthryl, indanyl, indenyl, xenyl etc.It can be abbreviated as " Ar ".

" heteroaryl " or " heteroaryl group " term, refer to stable aromatics 5-to 14-unit's monocycle shape or polycyclic unit price or divalent group, it can comprise one or more through condensing or the ring of bridge joint, 5-to 7-unit monocycle shape or 7-to 10-unit bicyclic radicals preferably, in ring, has one to four heteroatoms that independently is selected from nitrogen, oxygen and sulphur, wherein any sulfur heteroatom can be randomly oxidized, and any nitrogen heteroatom can be randomly oxidized or quaternized.Unless otherwise, otherwise heteroaryl ring can obtain any suitable heteroatoms or the connection of carbon atom place of stable structure in meeting, and if be substituted, then can obtain any suitable heteroatoms or the replacement of carbon atom place of stable structure in meeting.For example and preferred heteroaryl, comprise furyl, thienyl, pyrryl,

Azoles base, thiazolyl, imidazolyl, pyrazolyl, different

Azoles base, isothiazolyl,

Di azoly, triazolyl, tetrazyl, thiadiazolyl group, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, indyl, azaindolyl, indolinyl, pseudoindoyl, benzofuryl, dihydro benzo furyl, benzothienyl, dihydrobenzo thienyl, indazolyl, benzimidazolyl-, benzothiazolyl, benzo

Azoles base, benzisoxa

Azoles base, benzopyrazoles base, benzo piperazine are muttered ketone, purine radicals, quinolizinyl, quinolyl, dihydroquinoline base, tetrahydric quinoline group, tetrahydroquinoxaline base, isoquinolyl, dihydro-isoquinoline base, tetrahydro isoquinolyl, cinnolinyl, dai piperazine base, quinazolyl, quinoxalinyl, naphthyridinyl, pteridine radicals, carbazyl, acridyl, luxuriant and rich with fragrance piperazine base, luxuriant and rich with fragrance thiazinyl with luxuriant and rich with fragrance

Piperazine base, acridine etc.

" heterocycle ", " heterocyclic group ", " heterocyclic radical " or " heterocyclic radical group " term, refer to stablize non-aromatics 5-to 14-unit's monocycle shape or polycyclic unit price or divalence ring, it can comprise one or more through condensing or the ring of bridge joint, 5-to 7-unit monocycle shape or 7-to 10-unit double-ring ring preferably, in ring, has one to three heteroatoms that independently is selected from nitrogen, oxygen and sulphur, wherein any sulfur heteroatom can be randomly oxidized, and any nitrogen heteroatom can be randomly oxidized or quaternized.Unless otherwise, otherwise heterocyclic ring can obtain any suitable heteroatoms or the connection of carbon atom place of stable structure in meeting, and if be substituted, then can obtain any suitable heteroatoms or the replacement of carbon atom place of stable structure in meeting.Give an example and preferred heterocycle, comprise pyrrolinyl, pyrrolidyl, pyrazolinyl, pyrazolidyl, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, THP trtrahydropyranyl, tetrahydro thiapyran base, tetrahydrofuran base, hexahydropyrimidine base, hexahydro-pyridazine base, 2,3-dihydro-1,4-benzo dioxine, 1,3-benzodioxole, 3,4-dihydro-2H-1, the 4-benzo

Piperazine 1,2,3,4-tetrahydroisoquinoline, N-ethyl-N '-methylbenzene-1,2-diamines, 1,2,3,4-tetrahydroquinoline etc.

" The compounds of this invention " term and suitable wording refer to comprise formula (I) compound as described herein, comprise its tautomer, prodrug, salt, particularly pharmacologically acceptable salt, with solvate and hydrate, so allow part at this paper.General and preferred situation is, The compounds of this invention and the chemical formula of censuring The compounds of this invention, should understand only to comprise its stable compound, and get rid of unstable compounds, comprise also right even unstable compounds may be considered to literal combined thing chemical formula.Similarly,, no matter itself whether be required protection, comprise its salt and solvate, so allow part at this paper to the denotion of intermediate.For clarity sake, when context so allowed, regular meeting pointed out in the text during particular case, but these situations only are illustrative, and also although not exclusively, when context so allows.

" optional " or " randomly " term refer to can or can not taking place of described subsequently incident or situation, and this description comprises the situation that this incident or situation wherein take place, and wherein nonevent situation.For example, " randomly substituted aryl " refers to that aryl can or can not be substituted, and specification sheets comprises substituted aryl and do not have substituent aryl.

" stable compound " or " stable structure " term refer to that compound is enough stable and exist in the reaction mixture, be separated to useful purity, and preparation become effectively treatment or diagnostic reagent.For example, having " valence link dangles " or be the compound of carboanion, is not the compound that the present invention comprises.

" be substituted " any or a plurality of hydrogen on the atom that term refers to group or part group, no matter clearly whether specify, the group that is selected from indicated substituting group group replaces, and its condition is, the normal valence link that can not surpass atom, and this replacement can obtain stable compound.If to substituent connection is to be shown the connection of crossing two atoms in the shack, then this kind substituting group can be bonded to any atom on the ring.Do not point out when listing substituting group this kind substituting group via and be bonded to atomic time of compound rest part, then this kind substituting group can be through planting any atom combination in the substituting group thus.For example, when substituting group is piperazinyl, piperidyl or tetrazyl, unless otherwise specified, otherwise this kind piperazinyl, piperidyl or tetrazyl, can be bonded to the rest part of The compounds of this invention via any atom in this kind piperazinyl, piperidyl or tetrazyl.Generally speaking, when any substituting group or group occurred surpassing one time in any composition or compound, its definition in each existence place was irrelevant with its definition in each other existence place.Therefore, for example, if group shows by 0 to 2 R ⁵Replace, then this kind group is randomly by paramount two R ⁵Group replaces, and R ⁵In each existence place is independently to be selected from possibility R ⁵Through the definition inventory.But this kind combination of described substituting group and/or parameter only can obtain just can allowing under the stable compound in this kind combination.

In a special specific embodiment, " pact " or " approximately " term, refer to special value or scope 20% in, preferably in 10%, and more preferably in 5%.

The productive rate of described herein each reaction is to represent with the per-cent of theoretical yield.

B. salt, prodrug, derivative and solvate term and usage

" prodrug " or " prodrug derivant " term refers to parent compound or active drug substance with covalent manner bonded derivative or carrier, and it is before showing its pharmacotoxicological effect, experiences at least some biotransformations.Generally speaking, this kind prodrug has can metabolic way splitted group, and in vivo promptly changes, and to produce parent compound, for example by the hydrolytic action in the blood, and generally comprises the ester class and the amide analogue of parent compound.Prodrug is that the purpose of side effect (for example toxicity) of the prescription (for example water solubility of Zeng Jiaing) of organ selectivity, improvement of action period, the improvement of bioavailability, prolongation with patient's acceptability of the chemical stability of improving, improvement and conformability, improvement and/or reduction is through allocating.Generally speaking, prodrug itself have weak or abiology active, and under general condition for stable.Prodrug can use methods known in the art, easily makes from parent compound, and described person among following for example, The textbook of medicinal design and development, Krogsgaard-Larsen and H.Bundgaard (writing), Gordon ﹠amp; Breach, 1991, the 5th chapter particularly: " design of prodrug and application "; The design of prodrug, H.Bundgaard (writing), Elsevier, 1985; Prodrug: part and eye Drug delivery, K.B.Sloan (writing), Marcel Dekker, 1998; Enzymology method, people such as K.Widder (writing), the 42nd volume, university press, 1985,309-396 page or leaf particularly; BurrgerShi medicineization Learn and drug discovery, the 5th edition, M.Wolff (writing), John Wiley ﹠amp; Sons, 1995, particularly the 1st roll up and 172-178 page or leaf and 949-982 page or leaf; Prodrug as novel transmission system, T.Higuchi and V.Stella (writing), Am.Chem.Soc., 1975; Biological reversible carrier in medicinal design, E.B.Roche (writing), Elsevier, 1987, its each part is all with its full text and for reference in this paper.

In " pharmaceutically acceptable prodrug " used herein term, the medicine that refers to The compounds of this invention, it is to be applicable to human and zootic tissue to contact in the scope of safe and reliable medical judgment, and invariably when toxicity, stimulation, supersensitivity effect etc., be accompanied by rational interests/risk ratio, and effective, and under possible situation zwitterionic form for the purposes that it was intended to.

" salt " term refers to the anionic form of parent compound, or at parent compound and suitably be the product of the reaction of the hydrochlorate of preparation parent compound or alkali salt between acid or the alkali.The salt of The compounds of this invention can be by conventional chemical process, and the parent compound that contains alkalescence or acidic moiety group certainly is synthetic.Generally speaking, salt be via the alkali that makes free state or sour parent compound and stoichiometry or with excessive inorganic or organic acid or the alkali that forms the salt of wanting, reaction in appropriate solvent or all kinds of SOLVENTS combination and making.

" pharmacologically acceptable salt " term refers to the salt of The compounds of this invention, and it is to be applicable to human and zootic tissue contact in the scope of safe and reliable medical judgment, and work as toxicity invariably, pungency, supersensitivity effect etc.Be accompanied by rational interests/risk ratio, be generally water or oil soluble or dispersibility, and effective for the purposes that it was intended to.This term comprises pharmaceutically acceptable acid additive salt and pharmaceutically acceptable base addition salt.When The compounds of this invention can free state alkali and salt form when using, in practicality, the use of this salt form is the use that is equivalent to this alkali form.The suitable inventory of salt for example can be consulted people such as S.M.Birge, J.Pharm.Sci., and 1977, 66, the 1-19 page or leaf, it is in view of the above with its full text and for reference in this paper.

" pharmaceutically acceptable acid additive salt " term, refer to that these salt are biological effectiveness and the character that keeps the alkali of free state, and it is on biology or can not be not expect in other respects, form with inorganic acids, hydrochloric acid for example, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, thionamic acid, nitric acid, phosphoric acid etc., and and organic acid formation, acetate for example, trichoroacetic acid(TCA), trifluoroacetic acid, hexanodioic acid, Lalgine, xitix, aspartic acid, Phenylsulfonic acid, phenylformic acid, the 2-acetoxy-benzoic acid, butyric acid, dextrocamphoric acid, camphorsulfonic acid, styracin, citric acid, glucosulfone acid, ethane sulfonic acid, L-glutamic acid, oxyacetic acid, Phosphoric acid glycerol esters, hemisulfic acid, enanthic acid, caproic acid, formic acid, FUMARIC ACID TECH GRADE, 2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, maleic acid, hydroxy-maleic acid, oxysuccinic acid, propanedioic acid, phenylglycollic acid, 1,3,5-trimethylbenzene sulfonic acid, methanesulfonic, naphthene sulfonic acid, nicotinic acid, the 2-naphthene sulfonic acid, oxalic acid, pamoic acid, pectic acid, phenylacetic acid, the 3-phenylpropionic acid, picric acid, trimethylacetic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succsinic acid, para-aminobenzenesulfonic acid, tartrate, right-toluenesulphonic acids, undecanoic acid etc.

" pharmaceutically acceptable base addition salt " term, refer to that these salt are biological effectiveness and the character that keeps the acid of free state, and it is on biology or can not be not expect in other respects, form with inorganic base, for example ammonia, or ammonium or metallic cation be oxyhydroxide, carbonate or the supercarbonate of sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminium etc. for example.Particularly preferred is ammonium, potassium, sodium, calcium and magnesium salts.Salt derived from pharmaceutically acceptable organic nontoxic alkali, comprise following salt, primary, the second month in a season and tertiary amines, quaternary ammonium compound, substituted amine, the amine that is substituted that comprises natural generation, cyclic amine, and deacidite, methylamine for example, dimethylamine, Trimethylamine 99, ethamine, diethylamine, triethylamine, Isopropylamine, tripropyl amine, Tributylamine, thanomin, diethanolamine, the 2-dimethylamino-ethanol, 2-diethylin ethanol, dicyclohexylamine, Methionin, arginine, Histidine, trimethyl-xanthine, sea crust amine, choline, trimethyl-glycine, quadrol, glucosamine, methyl glucoside amine, Theobromine, purine, piperazine, piperidines, N-ethylpiperidine, the tetramethyl-ammonium compound, the tetraethyl ammonium compound, pyridine, N, the N-xylidene(s), the N-methyl piperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N, N-dibenzyl phenylethylamine, 1-Chinese ephedra amine, N, N '-dibenzyl-ethylenediamin, versamid 900 etc.Preferred especially organic nontoxic alkali is Isopropylamine, diethylamine, thanomin, Trimethylamine 99, dicyclohexylamine, choline and trimethyl-xanthine.

" solvate " term refers to the physics association of compound and one or more solvent molecule, or by solute (for example formula (I) compound) and the solvent formed variable stoichiometric mixture of water, ethanol or acetate for example.This physics association can relate in various degree ionic and covalently bound, comprises hydrogen bond.In some cases, solvate can separate, for example when one or more solvent molecule is merged in the lattice of crystalline solid.Generally speaking, selected solvent can not disturb the biologic activity of solute.Solvate is to comprise solution and separable solvate.The representative solvents compound comprises hydrate, ethylate, methylate etc.

" hydrate " term refers to that wherein solvent molecule is H ₂The solvate of O.

The compounds of this invention as discussed below, comprise the alkali or the acid of its free state, its salt, solvate and prodrug, and can in its structure, comprise sulphur atom or quaternised nitrogen-atoms through oxidation, although do not enunciate or show, its pharmaceutically acceptable form particularly.This kind form, particularly pharmaceutically acceptable form is comprised with the appended claim of literary composition.

C. isomer term and usage

" isomer " term refers to have same atoms number and kind, and therefore same molecular amount, but about its atom arrangement or different compound of configuration spatially, this term comprises steric isomer and geometrical isomer.

The term of " steric isomer " or " optical isomer ", refer to stable isomer, it has at least one chiral atom or restriction rotation, and causes vertical unsymmetrical plan (for example some biphenyl class, propadiene class and spirans), and can make plane polar biased light rotation.Because asymmetric center and other chemical structures are present in the The compounds of this invention, it can cause steric isomerism, so the present invention comprises steric isomer and composition thereof.The compounds of this invention and salt thereof are to comprise unsymmetrical carbon, and therefore can single stereoisomers, racemoid, and exist with the mixture of enantiomer and diastereomer.On the typical case, this kind compound is to be made into racemic mixture.But if need, this kind compound can be prepared to and be separated into pure stereoisomers, promptly becomes indivedual enantiomers or diastereomer, or becomes the mixture that is rich in steric isomer.As discussing hereinafter in more detail, indivedual steric isomers of compound are by synthetic from containing the optical activity initial substance of wanting chiral centre to some extent, or by preparation chirality isomerism mixture of products, then separate or fractionation, for example change into the mixture of diastereomer, then separate or recrystallization chromatographic technique, use the chiral separation agent, or on the chirality chromatography column, directly separate enantiomer and make.Specific stereochemical initial compounds is for no matter being commercial getting, or makes by method hereinafter described, and splits by the technology of this area routine.

" enantiomer " term refers to a pair of steric isomer that can not overlapping mirror image of being each other.

The term of " diastereoisomer " or " diastereomer " refers to not be each other the optical isomer of mirror image.

The term of " racemic mixture " or " racemoid " refers to contain the mixture of indivedual enantiomers of moiety.

" non-racemic mixture " term refers to contain the mixture of indivedual enantiomers of unequal part.

" geometrical isomer " term, refer to desmotrope, it is owing to cause around two keys (for example cis-2-butene and trans-2-butene) or the restriction rotary freedom in ring texture (for example cis-1,3-dichloro tetramethylene and anti-form-1,3-dichloro tetramethylene).Because carbon-to-carbon two (alkene) connection, the two keys of C=N, ring texture etc. can be present in the The compounds of this invention, arrange various stable geometrical isomers that caused and composition thereof so the present invention comprises each around these pairs key and the substituting group in these ring texturees.Suitable/anti-usage that substituting group and isomer are to use or use E or Z system censure, and wherein " E " term refers to the higher order substituting group on the opposition side of this pair key, and " Z " term refers to that the higher order substituting group is on the same side of this pair key.Discussing fully of E and Z isomery is provided in J.March, High Deng organic chemistry: reaction, mechanism and structure, the 4th edition, John Wiley ﹠amp; Sons, in 1992, it is in view of the above with it in full and for reference in this paper.Several following embodiment are expression single E isomer, single Z isomer and E/Z mixture of isomers.The mensuration of E and Z isomer can realize by analytical procedure, for example the x-radiocrystallgraphy, ¹H-NMR reaches ¹³C-NMR.

Some The compounds of this invention can more than one tautomeric form exist.As indicated above, The compounds of this invention comprises all this kind tautomers.

The biology of compound known in this field and pharmacological activity are to the stereochemistry sensitivity of compound.Therefore, for example, enantiomer often shows significantly different biologic activity, comprise the difference on the pharmacokinetic property, comprise metabolism, protein bound etc., and the difference on the pharmacological property, comprise shown active type, active, toxic degree etc.Therefore, those of ordinary skill in the art will recognize that a kind of enantiomer can maybe can show advantageous effect than the tool activity, when being rich in respect to another kind of enantiomer or when with another kind of stage enantiomer separation.In addition, how since then those of ordinary skill in the art will know the knowledge of disclosure and prior art, separation, enrichment or optionally prepare the enantiomer of The compounds of this invention.

Therefore, though can use the racemic form of medicine, it is often ineffective than pure medicine on the administration equivalent chirality isomery; In fact, in some cases, enantiomer can be on the pharmacology not active, and only just uses simple thinner as.For example, though ibuprofen (ibuprofen) is formerly with the racemoid administration, but confirmed that having only the S-isomer of ibuprofen is effectively as antiphlogistic (still, in Isobuytel Benzene acid situation in, though the R-isomer is not for active, but it is to be converted to the S-isomer in vivo, and therefore, the speed of action of the racemic form of this medicine is to be lower than pure S-isomer).In addition, the pharmacological activity of enantiomer can have the unique biological activity.For example, the S-Trolovol is the therapeutical agent of chronic arthritis, yet the R-Trolovol is poisonous.In fact, some purified enantiomers have the advantage better than racemoid because reported purified individual isomers and racemic mixture relatively, have faster through the skin transmission rate.Consult United States Patent (USP) 5,114,946 and 4,818,541.

Therefore, if a kind of enantiomer is compared to another kind of enantiomer, on the pharmacology than tool activity, low toxicity or in health, have preferred distribution, then preferentially this enantiomer of administration is more useful in the treatment.Mode according to this, the patient of experience treatment is exposed to low medicine total dose and enantiomer than the inhibitor of the possible poisonous or another kind of enantiomer of low dosage.

Pure enantiomer or the mixture of the enantiomer of wanting excessive (ee) or enantiomeric purity, its preparation is separation or the fractionation by those of ordinary skill in the art known many (a) enantiomer, or (b) one or more or its combination in the enantio-selectivity synthetic method realizes.These method for splitting generally are to rely on the chirality identification, and comprise that the chromatography, the enantio-selectivity main body-object that for example use chiral stationary phase are compound, use chiral adjuvant fractionation or synthetic, enantio-selectivity is synthetic, enzyme and fractionation of non-enzyme kinetics or the effect of spontaneous enantio-selectivity crystallization.This kind method is to be disclosed in prevailingly Chiral separation technology: practical approach(the 2nd edition), G.Subramanian (writing), Wiley-VCH, 2000; T.E.Beesley and R.P.W.Scott, The chirality chromatography, John Wiley ﹠amp; Sons, 1999; And Satinder Ahuja, Chiral separation by chromatography, Am.Chem.Soc. is in 2000.In addition, about enantiomer excessive or purity quantitatively, similar known method is arranged, for example GC, HPLC, CE or NMR, and the appointment of absolute configuration and conformation, for example CD ORD, X-radiocrystallgraphy or NMR.

Generally speaking, all tautomeric forms of chemical structure or compound and isomeric form and mixture, no matter be indivedual geometrical isomers or steric isomer or racemize or non-racemic mixture, all involved, clearly indicate specific stereochemistry or isomeric form unless in compound title or structure, have.Generally speaking, when racemic mixture when splitting, a kind of enantiomer is preferred.

D. medical administration and diagnosis and treatment term and usage

" patient " term comprises the mankind and non-human mammal.

" significant quantity " term refers to the amount according to The compounds of this invention, and by with regard to administration or the use, it is to be enough to realize desired effect or result with regard to it.Based on context, the significant quantity term can comprise pharmaceutically significant quantity or diagnosis go up significant quantity or with its synonym.

The term of " pharmaceutically significant quantity " or " significant quantity in the treatment " refers to the amount according to The compounds of this invention, when it is had the patient who needs by administration, is to be enough to realize that this compound has morbid state, symptom or the treatment of conditions of usability to it.This kind amount is biology or the medical effect that is enough to draw tissue, system or patient that researchist or clinicist look for.Constitute treatment go up significant quantity according to the The compounds of this invention amount, change according to some factors, for example compound and biologic activity thereof, the composition that is used for administration, administration time, route of administration, compound discharge rate, treatment perdurability, the morbid state of being treated or illness type and seriousness thereof, the medicine that merges or use simultaneously with The compounds of this invention, and patient's age, body weight, general health state, sex and diet.Significant quantity can be made a decision about its own knowledge, prior art and present disclosure by those of ordinary skill in the art routinely in this kind treatment.

" significant quantity in the diagnosis " term refers to the amount according to The compounds of this invention, in the time of in it is used in diagnostic method, device or detects, is to be enough to realize this diagnostic method, device or to detect the necessary diagnosis effect or the biologic activity of wanting wanted.This kind amount is to be enough to draw biology or medical effect at diagnostic method, device or in detecting, and it can be included among the patient or or biology in vivo tissue or the system or medical effect in vitro, and it is looked for for researchist or clinicist.Constitute diagnosis go up significant quantity according to the The compounds of this invention amount, change according to some factors, for example compound and biologic activity thereof, employed diagnostic method, device or detection, the medicine and other compounds that are used for composition, administration time, route of administration, compound discharge rate, the administration perdurability of administration, merge or use simultaneously with The compounds of this invention, and if the patient then is patient's age, body weight, general health state, sex and diet for the object of diagnosis administration.Significant quantity can make a decision about its own knowledge, prior art and present disclosure routinely by general those of ordinary skill in the art in this kind diagnosis.

" adjusting " term refers to that compound changes the ability of glucocorticoid receptor function, by for example being bonded to glucocorticoid receptor and stimulating or suppress its functional effect.

In the context of describing according to The compounds of this invention, " conditioning agent " term refers to regulate the compound of glucocorticoid receptor function.Therefore, conditioning agent includes but not limited to agonist, partial agonist, antagonist and partial antagonist.

In the context of describing according to The compounds of this invention, " agonist " term refers to when being bonded to glucocorticoid receptor, can improve or increase the compound of glucocorticoid receptor function.Therefore, agonist comprises partial agonist and full agonist.

In the context of describing according to The compounds of this invention, " full agonist " term refers to cause from glucocorticoid receptor the compound of maximal stimulation effect, even go back right when glucocorticoid receptor exists as unnecessary (unoccupied).

In the context of describing according to The compounds of this invention, " partial agonist " term refers to cause from glucocorticoid receptor the compound of maximal stimulation effect, even also right under the saturated concentration of the glucocorticoid receptor that is enough to make existence.

In the context of describing according to The compounds of this invention, " antagonist " term refers to directly or indirectly to suppress or the compound of oppressive glucocorticoid receptor function.Therefore, antagonist comprises partial antagonist and complete antagonist.

In the context of describing according to The compounds of this invention, " antagonist fully " term refers to cause from glucocorticoid receptor the compound of maximum retarding effect, even go back right when glucocorticoid receptor exists as unnecessary (unoccupied).

In the context of describing according to The compounds of this invention, " partial antagonist " term refers to cause from glucocorticoid receptor the compound of maximum retarding effect, even also right under the saturated concentration of the glucocorticoid receptor that is enough to make existence.

" treat " or the term of " treatment " refers to the treatment of morbid state among the patient, and comprise:

(i) the preventing disease state takes place in the patient, and particularly working as this kind patient is in heredity or this morbid state is easily suffered from other aspects, but is not diagnosed as yet when having this disease;

(ii) suppress or improve morbid state among the patient, promptly contain or its development of slowing down; Or

(iii) alleviate the morbid state among the patient, promptly cause the degeneration or the healing of morbid state.

The general synthetic method of preparation formula (IA) and formula (IB) compound

The present invention also provides the preparation formula (IA) and (IB) method of compound.In all flow processs, unless otherwise specified, otherwise the A in the chemical formula hereinafter, B, C, D, E, R ¹, R ²And R ³, will have formula of the present invention mentioned above (IA) and (IB) in A, B, C, D, E, R ¹, R ²And R ³Meaning.Employed intermediate in the The compounds of this invention preparation, perhaps commercial getting, or easily by the known method preparation of those of ordinary skill in the art.

Optimum reaction conditions and reaction times can change according to employed specific reactants.Unless otherwise, otherwise solvent, temperature, pressure and other reaction conditionss can easily select by those of ordinary skill in the art.Particular step is provided in the synthetic embodiment part.Typically, if need, then reaction progress can pass through thin layer chromatography (TLC) and monitors, and intermediate and product can be on silica gel by chromatography and/or pass through recrystallization purifying.

Formula (IA) compound can be by the method preparation of being summarized among the flow process I.

Flow process I

As shown in flow process I, nitrile is with suitable reductive agent, and hydrogenation di-isopropyl aluminium for example for example reduces among methylene dichloride or the THF at appropriate solvent, to produce aldehyde (III).The condensation of aldehydes is the routine of this area, and [1,3] dithian-2-base trimethyl silyl negatively charged ion can with aldehyde (III), in for example condensation in THF or the ether of appropriate solvent, so that thioketene acetal (V) to be provided.Two keys of thioketene acetal (V) in triethyl-silicane and suitable acid for example in the presence of the TFA, in the appropriate solvent reductive action in the methylene dichloride for example, provide sulfo-acetal (VI).Sulfo-acetal (VI) at the appropriate solvent deprotection in the acetonitrile for example, provides aldehyde (VII) in the presence of methyl iodide.Nucleophilicity to aldehyde adds as this area routine, and the trifluoromethyl negatively charged ion can be added in the aldehyde (VII), for example in THF or the ether, provides secondary alcohol (VIII) at appropriate solvent.Alcohol (VIII) in the suitable oxidizing agent for example Dess-Martin periodinane or Manganse Dioxide exist down, in the appropriate solvent oxygenizement in methylene dichloride or the acetone for example, provide ketone (IX).Ketone (IX) and suitable organometallic reagent R ³M, for example refined reagent of Green (M is MgBr or MgCl), or organolithium reagent (M is Li) for example reacts in THF or the ether at appropriate solvent, and desired formula (IA) compound is provided, and wherein C is CH ₂, D is CR ⁴R ⁵(R wherein ⁴Be CF ₃, and R ⁵Be OH), and E is a chemical bond.Perhaps, formula (IA) compound, when C is a chemical bond, D is CR ⁴R ⁵(R wherein ⁴Be CF ₃, and R ⁵Be OH), and E is chemical bond, can be via from aldehyde (III), and reach and (h) make according to the step (f) shown in the flow process I, (g).

Ketone (IX) and sulphur ylide compound for example react in THF or the ether at appropriate solvent, and epoxide (XII) is provided.The division of epoxide is to be this area routine, and can realize by nucleophilic reagent or organometallic reagent addition.Epoxide (XII) can be by adding organometallic reagent R ³M, for example refined reagent of Green (M is MgBr or MgCl), or organolithium reagent (M is Li) for example divides in THF or the ether at appropriate solvent.The division of epoxide (XII) also can via with nucleophilic reagent R ³H, for example amine (R wherein ³Be NR ⁶R ⁷), alcohols (R wherein ³Be OR ⁸) or thio-alcohol (R wherein ³Be SR ⁹), no matter use or do not use alkali, in for example reaction and realize that so that formula (IA) compound to be provided, wherein C is CH among DMF or the DMSO of appropriate solvent ₂, D is CR ⁴R ⁵(R wherein ⁴Be CF ₃, and R ⁵Be OH), and E is CH ₂Perhaps, formula (IA) compound, wherein C is a chemical bond, D is CR ⁴R ⁵(R wherein ⁴Be CF ₃, and R ⁵Be OH), and E is CH ₂, can be via with aldehyde (III) beginning, and obtain according to the step (f) shown in the flow process I, (g), (i) and (j).

Aldehyde (VII) and suitable organometallic reagent R ³M, for example refined reagent of Green (M is MgBr or MgCl), or organolithium reagent (M is Li) for example reacts in THF or the ether at appropriate solvent, and secondary alcohol (XIV) is provided.Alcohol (XIV) in the suitable oxidizing agent for example Dess-Martin periodinane exist down, in the appropriate solvent oxygenizement in methylene dichloride or the acetone for example, provide ketone (XV).Ketone (XV) and (trifluoromethyl) trimethyl silyl, for example tetrabutylammonium exists down in suitable fluorine source, in for example reaction in THF or the ether of appropriate solvent, provides formula (IA) compound, and wherein C is CH ₂, D is CR ⁴R ⁵(R wherein ⁴Be CF ₃, and R ⁵Be OH), and E is a chemical bond.Perhaps, formula (IA) compound, wherein C is a chemical bond, D is CR ⁴R ⁵(R wherein ⁴Be CF ₃, and R ⁵Be OH), and E is chemical bond, can be via with aldehyde (III) beginning, and obtain according to the step (e) of flow process I, (k) and (l).

Formula (IB) compound can be made via the method for being summarized among the flow process II.

Flow process II

The reaction of nitrile and the refined reagent of Green is to be this area routine.As shown in flow process II, nitrile (II) and the refined reagent R of Green ⁴M (M is MgBr or MgCl) for example reacts in THF or the ether at appropriate solvent, and ketone (XVII) is provided.Ketone (XVII) and organometallic reagent R ³M, for example refined reagent of Green (M is MgBr or MgCl), or organolithium reagent (M is Li) for example reacts in THF or the ether at appropriate solvent, and formula (IB) compound is provided.

Formula (IB) compound also can be made by the method for being summarized among the flow process III.

Flow process III

As shown in flow process III, aldehyde (VII) and suitable organometallic reagent R ⁴M, the refined reagent of Green (M is MgBr or MgCl) for example for example reacts in THF or the ether at appropriate solvent, and secondary alcohol (XVIII) is provided.Alcohol (XVIII) in the suitable oxidizing agent for example Dess-Martin periodinane exist down, in the appropriate solvent oxygenizement in methylene dichloride or the acetone for example, provide ketone (XIX).Ketone (XIX) and suitable organometallic reagent R ³M, for example refined reagent of Green (M is MgBr or MgCl), or organolithium reagent (M is Li) for example reacts in THF or the ether at appropriate solvent, and formula (IB) compound is provided, and wherein C is CH ₂, D is CR ⁴R ⁵(R ⁵Be OH), and E is a chemical bond.

Ketone (XIX) and sulphur ylide compound for example react in THF or the ether at appropriate solvent, and epoxide (XX) is provided.Epoxide (XX) can by with organometallic reagent R ³M, for example refined reagent of Green (M is MgBr or MgCl), or organolithium reagent (M is Li) is in for example addition division in THF or the ether of appropriate solvent.The division of epoxide (XX) also can via with nucleophilic reagent R ³H, for example amine (R wherein ³Be NR ⁶R ⁷), alcohols (R wherein ³Be OR ⁸) or thio-alcohol (R wherein ³Be SR ⁹), no matter use or do not use alkali, in for example reaction and realize that so that formula (IB) compound to be provided, wherein C is CH among DMF or the DMSO of appropriate solvent ₂, D is CR ⁴R ⁵(R wherein ⁵Be OH), and E is CH ₂Perhaps, formula (IB) compound, wherein C is a chemical bond, D is CR ⁴R ⁵(R wherein ⁵Be OH), and E is CH ₂Can be via with ketone (XVII) beginning, and according to step (d) with (e) obtain.

A kind of method for preparing benzotriazole nitrile (XXV) and benzoglyoxaline nitrile (XXVI) is to be summarized among the flow process IV.

Flow process IV

Such as among the flow process IV general introduction, randomly substituted chloronitrobenzene formonitrile HCN (XXI) is and substituted aniline (XXII) randomly, exist down in diisopropylethylamine, for example react among DMF or the DMA at appropriate solvent, so that randomly substituted amino nitrobenzonitrile (XXIII) to be provided.Amido nitrobenzonitrile (XXIII) is to be reduced into corresponding diaminobenzene formonitrile HCN (XXIV) under the hydrogen transference condition.Randomly substituted diaminobenzene formonitrile HCN (XXIV) is and SODIUMNITRATE to react in acetate, so that randomly substituted benzotriazole (XXV) to be provided.Will be randomly substituted two amido cyanobenzene (XXIV) and trimethyl orthoformates, in suitable acid for example right-there is heating down in toluenesulphonic acids, so that randomly substituted benzoglyoxaline (XXVI) to be provided.

Indazole nitrile (II), wherein A is N, and B is CH, is according to people such as Hall, Syn.Commun., 1997,27 (7), the known steps of 1199-1207 page or leaf is made.Indoles nitrile (II), wherein A is CH, and B is CH, is according to people such as Antilla, J.Am.Chem.Soc., 2002, 124, the known steps of 11684-11688 page or leaf is made.

For the present invention is understood more fully, following embodiment is disclosed.These embodiment are for reaching the purpose of the explanation specific embodiment of the invention, but not desire to be interpreted as limiting the scope of the invention by any way, because understand that as those of ordinary skill in the art particular agent or condition can be by the needs of individual compound through revising.Employed initial substance or commercial getting, or easily by those of ordinary skill in the art's system from the commercial material that gets.

Embodiment

EXPERIMENTAL EXAMPLE

Embodiment 1:2,2,2-three fluoro-1-phenyl-1-(1-phenyl-1H-indazole-5-yl) ethanol

Step (a): under 0 ℃, to 1-phenyl-1H-indazole-5-nitrile (12.58 gram, 57.38 mmoles) at 300 milliliters of CH ₂Cl ₂In solution in, add DIBAL-H (1M, in THF, 80.33 milliliters, 80.33 mmoles).Formed yellow suspension was stirred 2 hours, then, pour in 150 milliliters of cold 1N HCl solution.Make biphasic system be cooled to 0 ℃, then, by adding saturated sodium bicarbonate (NaHCO ₃) aqueous solution alkalizes to pH 8.With water layer with three parts of each CH of 100 milliliters ₂Cl ₂Extraction.The organic phase that makes merging is with sodium sulfate (Na ₂SO ₄) drying, filter, then vacuum concentration.Make crude material pass through quick purification by silica gel column chromatography (with 100%-80% hexane/EtOAc wash-out).Obtain desired product 1-phenyl-1H-indazole-5-formaldehyde, be faint yellow solid (8.8 grams, 69% productive rate; M+H ⁺: 223).

Step (b): under 0 ℃, in the solution of 1-phenyl-1H-indazole-5-formaldehyde (6.0 grams, 27.0 mmoles) in 50 milliliters of THF, add TMSCF ₃Solution in THF (4.5 milliliters, 31.8 mmoles).Formed yellow solution was stirred 15 minutes down at 0 ℃, then, interpolation tetrabutylammonium (TBAF) (1M, in THF, 7.8 milliliters, 7.8 mmoles).Make reaction mixture be warmed to room temperature, then, restir 14 hours.Make THF vacuum-evaporation, and formed residue is dissolved among 100 milliliters of EtOAc, with three parts of each 25 ml waters, and the washing of a 25 mL of saline, with dried over sodium sulfate, filter, and vacuum evaporating solvent.Make crude material pass through quick purification by silica gel column chromatography (with 80% hexane/EtOAc wash-out).Obtain desired product 2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol is faint yellow solid (7.1 grams, 88.0% productive rate; M+H ⁺: 293).

Step (c): make Dess-Martin periodinane (11.9 grams, 28.0 mmoles) with 2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (7.0 grams, 24.0 mmoles) is at 100 milliliters of CH ₂Cl ₂In suspension at room temperature stirred 12 hours.Reaction mixture is added in 150 milliliters of hexanes, and with formed white depositions process CELITE

The pad of flocculating aids filters.The organic solution that merges is washed with three parts of each 25 milliliters saturated sodium bicarbonate aqueous solutions and 25 mL of saline,, filter with dried over sodium sulfate, and vacuum evaporating solvent.Make crude material pass through quick purification by silica gel column chromatography (with 85% hexane/EtOAc wash-out).Obtain desired product 2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethyl ketone is white solid (6.3 grams, 91.0% productive rate; M+H ⁺: 291).

Step (d): at room temperature,, in the solution of 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethyl ketones (50.0 milligrams, 0.2 mmole) in 0.5 milliliter of THF, add phenyl-magnesium-bromide (1.0M, 1.0 milliliters, 1.0 mmoles) to 2,2.Solution was stirred 12.0 hours under this temperature.With 2 milliliters of saturated ammonium chloride (NH4Cl) aqueous solution and 3.0 ml waters, make the stopping of reaction.With three parts of each 5 milliliters of EtOAc extractions, and the organic layer that makes merging filters with dried over sodium sulfate with water layer, and vacuum evaporating solvent.Make crude material pass through quick purification by silica gel column chromatography (with 100%-85% hexane/EtOAc wash-out).Obtain desired product 2,2,2-three fluoro-1-phenyl-1-(1-phenyl-1H-indazole-5-yl) ethanol, for white solid (51.0 milligrams, 80% productive rate; M+H ⁺: 369).

Following embodiment is according to about the illustrated step of embodiment 1 step (d), uses the refined or equivalent organometallic reagent of corresponding Green synthetic.The yield percentage of reactant and M+H ⁺Be presented at parenthetic.

1-biphenyl-3-base-2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (72%, M+H ⁺: 445);

1-(3, the 4-difluorophenyl)-2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (63%, M+H ⁺: 405);

1-(3, the 5-difluorophenyl)-2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (82%, M+H ⁺: 405);

1-(3-chloro-5-fluorophenyl)-2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (66%, M+H ⁺: 421);

1-(4-chloro-3-aminomethyl phenyl)-2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (72%, M+H ⁺: 417);

1-(3-chloro-phenyl-)-2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (69%, M+H ⁺: 403);

1-(3-chloro-4-fluorophenyl)-2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (75%, M+H ⁺: 421);

1-(4-chloro-3-fluorophenyl)-2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (68%, M+H ⁺: 421);

1-(3, the 5-dichlorophenyl)-2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (48%, M+H ⁺: 438);

2,2, and 2-three fluoro-1-naphthalene-1-base-1-(1-phenyl-1H-indazole-5-yl) ethanol (80%, M+H ⁺: 419);

2,2, and 2-three fluoro-1-(3-fluorophenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol (69%, M+H ⁺: 387);

2,2, and 2-three fluoro-1-(4-methylnaphthalene-1-yl)-1-(1-phenyl-1H-indazole-5-yl) ethanol (74%, M+H ⁺: 433);

1-(2,3-dihydrobenzo [1,4] dioxine-6-yl)-2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (76%, M+H ⁺: 427);

1-(3, the 4-dichlorophenyl)-2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (26%, M+H ⁺: 427);

2,2, and 2-three fluoro-1-(4-fluorophenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol (55%, M+H ⁺: 387);

2,2, and 2-three fluoro-1-(3-fluoro-4-aminomethyl phenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol (83%, M+H ⁺: 401);

1-benzo [1,3] dioxole-5-base-2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (39%, M+H ⁺: 413);

1-(4-chloro-phenyl-)-2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (76%, M+H ⁺: 403);

2,2, and 2-three fluoro-1-(3-morpholine-4-ylmethyl phenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol (78%, M+H ⁺: 468);

2,2, and 2-three fluoro-1-(4-morpholine-4-ylmethyl phenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol (59%, M+H ⁺: 468);

2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl)-1-(2) ethanol (80%, M+H ⁺: 411);

2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl)-1-(2,4, the 6-trimethylphenyl) ethanol (83%, M+H ⁺: 411);

1-(the 4-tertiary butyl-2,6-3,5-dimethylphenyl)-2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (20%, M+H ⁺: 453);

2,2, and 2-three fluoro-1-(3-p-methoxy-phenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol (79%, M+H ⁺: 399);

1-(3, the 5-3,5-dimethylphenyl)-2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (67%, M+H ⁺: 397);

2,2, and 2-three fluoro-1-(4-methoxyl group-3,5-3,5-dimethylphenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol (73%, M+H ⁺: 427);

2,2, and 2-three fluoro-1-(4-p-methoxy-phenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol (65%, M+H ⁺: 399);

1-(3, the 4-3,5-dimethylphenyl)-2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (73%, M+H ⁺: 397);

2,2, and 2-three fluoro-1-(3-fluoro-4-p-methoxy-phenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol (70%, M+H ⁺: 417);

2,2, and 2-three fluoro-1-(5-fluoro-2-p-methoxy-phenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol (77%, M+H ⁺: 417);

1-(2, the 5-Dimethoxyphenyl)-2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (89%, M+H ⁺: 429);

2,2, and 2-three fluoro-1-(2-morpholine-4-ylmethyl phenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol (76%, M+H ⁺: 468);

1-biphenyl-2-base-2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (73%, M+H ⁺: 445);

2,2, and 2-three fluoro-1-(4-fluoronaphthalene-1-yl)-1-(1-phenyl-1H-indazole-5-yl) ethanol (86%, M+H ⁺: 437);

2,2, and 2-three fluoro-1-(6-methoxynaphthalene-2-yl)-1-(1-phenyl-1H-indazole-5-yl) ethanol (82%, M+H ⁺: 449);

2,2, and 2-three fluoro-1-naphthalene-2-base-1-(1-phenyl-1H-indazole-5-yl) ethanol (73%, M+H ⁺: 419);

2,2, and 2-three fluoro-1-(2-methylnaphthalene-1-yl)-1-(1-phenyl-1H-indazole-5-yl) ethanol (47%, M+H ⁺: 433);

1-benzo [b] thiene-3-yl--2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (43%, M+H ⁺: 425); And

2,2, and 2-three fluoro-1-(6-fluorine pyridine-2-yl)-1-(1-phenyl-1H-indazole-5-yl) ethanol (35%, M+H ⁺: 388).

Split into (+)-with (-) enantiomer be at CHIRALCEL by chirality HPLC ^TMOn the AD-H post, realize with 20% Virahol-hexane wash-out.

Embodiment 2:2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-phenylethyl alcohol

Step (a): under 0 ℃, to 1-(4-fluorophenyl)-1H-indazole-5-nitrile (2.0 gram, 8.43 mmoles) at 100 milliliters of CH ₂Cl ₂In solution in, add DIBAL-H (1M, in THF, 12.6 milliliters, 12.6 mmoles).Formed yellow suspension was stirred 2 hours, then, pour in 25 milliliters of cold 1N HCl solution.Make biphasic system be cooled to 0 ℃, then, alkalize to pH 8 by adding saturated sodium bicarbonate aqueous solution.With water layer with three parts of each 50 milliliters of CH ₂Cl ₂Extraction.The organic phase that makes merging is filtered with dried over sodium sulfate, then, and vacuum concentration.Make crude material pass through quick purification by silica gel column chromatography (with 100%-80%EtOAc/ hexane wash-out).Obtain desired product 1-(4-fluorophenyl)-1H-indazole-5-formaldehyde, be faint yellow solid (1.4 grams, 69% productive rate; M+H ⁺: 241).

Step (b): under 0 ℃, in the solution of 1-(4-fluorophenyl)-1H-indazole-5-formaldehyde (1.4 grams, 6 mmoles) in 10 milliliters of THF, add TMSCF ₃(1.3 grams, 9 mmoles).Formed yellow solution was stirred 15 minutes down at 0 ℃, then, add TBAF solution (15 milliliters, 15 mmoles).Make reaction mixture be warmed to room temperature, then restir is 14 hours.Make THF vacuum-evaporation, and formed residue is dissolved among 100 milliliters of EtOAc,,, filter with dried over sodium sulfate with three parts of each 25 ml waters and the washing of 25 mL of saline, and vacuum evaporating solvent.Make crude material pass through quick purification by silica gel column chromatography (with 95%-70%EtOAc/ hexane wash-out).Obtain desired product 2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol, be faint yellow solid (1.3 grams, 72% productive rate; M+H ⁺: 311).

Step (c): at room temperature, with Dess-Martin periodinane (360 milligrams, 0.85 mmole) and 2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (217 milligrams, 0.7 mmole) is at 3 milliliters of CH ₂Cl ₂In suspension stirred 12 hours.Reaction mixture is added in 1 milliliter of hexane, and makes formed white depositions through CELITE

The pad of flocculating aids filters.The organic solution that merges is washed with three milliliters sodium bicarbonate and 5 mL of saline,, filter with dried over sodium sulfate, and vacuum evaporating solvent.Make crude material pass through quick purification by silica gel column chromatography (with 80%EtOAc/ hexane wash-out).Obtain desired product 2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethyl ketone, for white solid (200 milligrams, 93.0% productive rate; M+H ⁺: 309).

Step (d): at room temperature,, 2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl to 2,2] in the solution of ethyl ketone (25.0 milligrams, 0.07 mmole) in 0.5 milliliter of THF, add phenyl-magnesium-bromide (1.0M, 0.5 milliliter, 5.0 mmoles).Solution was stirred 12.0 hours under this temperature.Make the stopping of reaction with 2 milliliters of saturated aqueous ammonium chlorides and 3.0 ml waters.With three parts of each EtOAc extractions of 5 milliliters, and the organic layer that makes merging filters with dried over sodium sulfate with water layer, and vacuum evaporating solvent.Make crude material pass through quick purification by silica gel column chromatography (with 100%-85%EtOAc/ hexane wash-out).Obtain desired product 2,2,2-three fluoro-1-phenyl-1-[1-(4-fluorophenyl)-1H-indazole-5-yls] ethanol, for white wax shape oil (25.0 milligrams, 99% productive rate; M+H ⁺: 387).

Following embodiment is according to about the illustrated step of embodiment 2 steps (d), uses the refined or equivalent organometallic reagent of corresponding Green, and is synthetic with the indazolone of suitable functional groupization.The yield percentage of reactant and M+H ⁺Be presented at parenthetic.

1-(3-chloro-4-fluorophenyl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (70%, M+H ⁺: 439);

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-naphthalene-1-base ethanol (97%, M+H ⁺: 437);

2,2,2-three fluoro-1-(4-fluoronaphthalene-1-yl)-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (94%, M+H ⁺: 455);

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(4-methylnaphthalene-1-yl) ethanol (58%, M+H ⁺: 451);

1-benzo [b] thiene-3-yl--2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (64%, 443);

1-(2,2-two fluoro-1,3-benzodioxole-4-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (55%; M+H ⁺: 467);

1-1,3-benzodioxole-4-base-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (62%; M+H ⁺: 432);

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1H-indoles-7-yl) ethanol (46%; M+H ⁺: 427);

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-Methyl-1H-indole-7-yl) ethanol (53%; M+H ⁺: 440);

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-Methyl-1H-indole-5-yl) ethanol; (62%; M+H ⁺: 440);

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-Methyl-1H-indole-6-yl) ethanol; (61%; M+H ⁺: 440);

4-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl } indoles-1-formic acid tertiary butyl ester (70%; M+H ⁺: 527);

1-methyl-4-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-quinoline-2-one-(27%; M+H ⁺: 469);

1-(3, the 4-dichlorophenyl)-2,2, and 2-three fluoro-1-(1-pyridine-2-base-1H-indazole-5-yl) ethanol (79%, M+H ⁺: 438);

1-(3-chloro-phenyl-)-2,2, and 2-three fluoro-1-(1-pyridine-2-base-1H-indazole-5-yl) ethanol (83%, M+H ⁺: 404);

1-(3, the 4-difluorophenyl)-2,2, and 2-three fluoro-1-(1-pyridine-2-base-1H-indazole-5-yl) ethanol (75%, M+H ⁺: 406);

2,2, and 2-three fluoro-1-phenyl-1-(1-pyridine-2-base-1H-indazole-5-yl) ethanol (87%, M+H ⁺: 370);

2,2,2-three fluoro-1-[1-(2-fluorophenyl)-1H-indazole-5-yl]-the 1-phenylethyl alcohol (87%, M+H ⁺: 387);

2,2,2-three fluoro-1-[1-(2-fluorophenyl)-1H-indazole-5-yl]-1-naphthalene-1-base ethanol (75%, M+H ⁺: 437);

2,2,2-three fluoro-1-(4-fluoronaphthalene-1-yl)-1-[1-(2-fluorophenyl)-1H-indazole-5-yl] ethanol (81%, M+H ⁺: 454);

2,2, and 2-three fluoro-1-phenyl-1-(1-p-tolyl-1H-indazole-5-yl) ethanol (77%, M+H ⁺: 383);

2,2,2-three fluoro-1-[1-(4-p-methoxy-phenyl)-1H-indazole-5-yl]-the 1-phenylethyl alcohol (73%, M+H ⁺: 399);

2,2, and 2-three fluoro-1-phenyl-1-(1-o-tolyl-1H-indazole-5-yl) ethanol (68%, M+H ⁺: 383);

2,2, and 2-three fluoro-1-naphthalene-1-base-1-(1-o-tolyl-1H-indazole-5-yl) ethanol (71%, M+H ⁺: 433);

2,2, and 2-three fluoro-1-(4-fluoronaphthalene-1-yl)-1-(1-o-tolyl-1H-indazole-5-yl) ethanol (65%, M+H ⁺: 451); And

1-[3-(2,5-dimethyl pyrrole-1-yl) phenyl]-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (70%, M+H ⁺: 462).

Embodiment 3:2,2,2-three fluoro-1-isoquinolyl-1-1-(1-phenyl-1H-indazole-5-yl) ethanol

Step (a): in 250 ml flasks, place 80 milliliters of CH ₂Cl ₂In 1-phenyl-1H-indazole-5-formaldehyde (4.0 gram, 1 equivalent).To wherein, drip BF ₃OEt ₂(2.5 milliliters, 1.1 equivalents).After 5 minutes, add 1,3-propane dithiol (1.9 milliliters, 1.1 equivalents), and reactant at room temperature stirred 18 hours.Remove volatile matter, and residue is developed with minimum acetonitrile, and filter, desired product 5-1 is provided, 3-dithian-2-base-1-phenyl-1H-indazole is faint yellow solid (4.1 grams, 72% productive rate; M+H ⁺: 313).

Step (b): under argon gas, in 25 milliliters of round-bottomed flasks, place the 5-1 among 3 milliliters of THF, 3-dithian-2-base-1-phenyl-1H-indazole (83 milligrams, 1 equivalent).Make it be cooled to-78 ℃, to wherein dripping n-BuLi (2.5M, in hexane, 0.12 milliliter, 1.1 equivalents).After 10 minutes, add 2-chlorine isoquinoline 99.9 (65 milligrams, 1.5 equivalents) with the solution in 1 milliliter of THF.Then, make reactant be warmed to room temperature.After 20 minutes, reactant is diluted with water, and extract with EtOAc.Make the organic substance drying of merging, and vacuum-evaporation.Make residue pass through the flash chromatography purifying, so that desired product 1-[2-(1-phenyl-1H-indazole-5-yl)-1,3-dithian-2-yl to be provided] isoquinoline 99.9, for yellow oil (113 milligrams, 96% productive rate; M+H ⁺: 440).

Step (c): in 100 milliliters of round-bottomed flasks, place the 1-[2-(1-phenyl-1H-indazole-5-yl)-1 in 5 milliliter of 10% methanol aqueous solution, 3-dithian-2-yl] isoquinoline 99.9 (113 milligrams, 1.0 equivalents), HgCl ₂(139 milligrams, 2.0 equivalents), HgO (56 milligrams, 1.0 equivalents).It was heated 4 hours under refluxing.Then, reactant is diluted with EtOAc, and cross filter solid.Solid is washed with EtOAc.Filtrate is transferred to separating funnel, and with sodium bicarbonate, sodium chloride saturated solution and EtOAc dilution.Remove organic layer, and with normal saline washing.Then, make the organic substance drying of merging, filter, and vacuum-evaporation.Make resistates pass through the flash chromatography purifying.Collect most of wash-out level part, and vacuum-evaporation, so that desired product isoquinolyl-1-(1-phenyl-1H-indazole-5-yl) ketone to be provided, for white solid (54 milligrams, 59% productive rate; M+H ⁺: 350).

Step (d): in 50 milliliters of round-bottomed flasks, place isoquinolyl-1-(1-phenyl-1H-indazole-5-yl) ketone (54 milligrams, 1 equivalent) among 2 milliliters of THF.Make it be cooled to 0 ℃, to wherein dripping trifluoromethyl trimethyl silyl (38 microlitres, 1.6 equivalents).After having added, reactant was stirred 30 minutes down at 0 ℃, to wherein adding TBAF (1.0M, in THF, 0.23 milliliter, 1.5 equivalents), and will stir 18 hours under the reactant room temperature.Then, reactant is diluted with water, and extract with EtOAc.Make the organism drying, filter, and vacuum-evaporation, and make residue pass through the flash chromatography purifying, desired product 2,2 is provided, 2-three fluoro-1-isoquinolyl-1-1-(1-phenyl-1H-indazole-5-yl) ethanol, for faint yellow solid (52 milligrams, 80% productive rate; M+H ⁺: 420).

Following embodiment is according to about the illustrated step of embodiment 3, according to step b), c) and d), use corresponding electrophilic reagent synthetic.The yield percentage of reactant and M+H ⁺Be presented at parenthetic.

2,2, and 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl)-1-quinolyl-4 ethanol (13%, M+H ⁺: 420).

Embodiment 4:1,1,1-three fluoro-3-phenyl-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol

Step (a): to iodate trimethylammonium sulphur

In (3.2 grams, 14.5 mmoles) suspension in 9.0 milliliters of DMSO, add NaH (0.6 gram, 14.5 mmoles).Formed solution was stirred 30 minutes under room temperature and argon atmosphere.The solution of this ylide compound (4.5 milliliters) is added into 2,2, in the solution of 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethyl ketone (2.0 gram, 6.9 mmoles) in 4.5 milliliters of DMSO, and formed solution was at room temperature stirred 1.5 hours.Reaction mixture is poured on 100 ml waters, and with three parts of each 75 milliliters of EtOAc extractions.The organic layer that merges is washed with 50 mL of saline,, filter with dried over sodium sulfate, and vacuum evaporating solvent.Make crude material pass through quick purification by silica gel column chromatography (with 100%-85% hexane/EtOAc wash-out).Obtain desired product 1-phenyl-5-(2-trifluoromethyl Oxyranyle)-1H-indazole, be white solid (0.8 gram, 36% productive rate; M+H ⁺: 305).

Step (b): in 1-phenyl-5-(2-trifluoromethyl the Oxyranyle)-solution of 1H-indazole (50.0 milligrams, 0.1 mmole) in 0.5 milliliter of THF, add phenyl-magnesium-bromide (1.0M, 1.3 milliliter, 1.3 mmoles), then, in sealed reaction tube, stirred 3 days down in 80 ℃.By adding 2.0 milliliters of saturated aqueous ammonium chlorides and 1 ml water, make the stopping of reaction.With three parts of each 5 milliliters of EtOAc aqueous layer extracted, and the organic layer that makes merging filters with dried over sodium sulfate, and vacuum evaporating solvent.Make crude material pass through quick purification by silica gel column chromatography (with 100%-85% hexane/EtOAc wash-out).Obtain desired product 1,1,1-three fluoro-3-phenyl-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol, for white solid (17 milligrams, 35.0% productive rate; M+H ⁺: 383).

Embodiment 5:1,1,1-three fluoro-3-(3-fluorophenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol

In 1-phenyl-5-(2-trifluoromethyl the Oxyranyle)-solution of 1H-indazole (50.0 milligrams, 0.1 mmole) in 0.5 milliliter of THF, add 3-fluorophenyl magnesium bromide (1.0M, 1.3 milliliters, 1.3 mmoles).Reaction mixture in sealed reaction tube, was stirred 3 days down in 80 ℃.By adding 2.0 milliliters of saturated aqueous ammonium chlorides and 1 ml water, make the stopping of reaction.With three parts of each 5 milliliters of EtOAc aqueous layer extracted, and the organic layer that makes merging filters with dried over sodium sulfate, and vacuum evaporating solvent.Make crude material pass through quick purification by silica gel column chromatography (with 100%-85% hexane/EtOAc wash-out).Obtain desired product 1,1,1-three fluoro-3-(3-fluorophenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol, for white solid (17 milligrams, 32.0% productive rate; M+H ⁺: 401).

Following embodiment is according to synthesizing about embodiment 5 illustrated steps.The yield percentage of reactant and M+H ⁺Be presented at parenthetic.

3-(3-chloro-2-fluorophenyl)-1,1, and 1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (37%, M+H ⁺: 435);

3-(4-chloro-3-fluorophenyl)-1,1, and 1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (29%, M+H ⁺: 435); And

3-(4-chloro-2-fluorophenyl)-1,1, and 1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (33%, M+H ⁺: 435).

Embodiment 6:1-[3,3,3-three fluoro-2-hydroxyl-2-(1-phenyl-1H-indazole-5-yl) propyl group]-1H-indoles-3-nitrile

In 1-phenyl-5-(2-trifluoromethyl the Oxyranyle)-solution of 1H-indazole (50.0 milligrams, 0.1 mmole) in 0.5 milliliter of THF, add (45.0 milligrams of indoles-3-nitrile, 0.3 mmole) with sodium ethylate (21 weight %, in ethanol, 0.13 milliliter, 0.30 mmole).Formed solution in sealed reaction tube, was stirred 12 hours down in 90 ℃.Make reaction mixture be cooled to room temperature, and add 2.0 ml waters.With two parts of each 5 milliliters of extracted with diethyl ether water layers.Merge organic layer, and Yi Shui and salt water washing, then,, and filter with dried over sodium sulfate.Vacuum is removed solvent by rotary evaporation.Make crude material pass through quick purification by silica gel column chromatography (with 95%-90% hexane/EtOAc wash-out).Obtain desired product 1-[3,3,3-three fluoro-2-hydroxyl-2-(1-phenyl-1H-indazole-5-yl) propyl group]-1H-indoles-3-nitrile, for white solid (20 milligrams, 27% productive rate; M+H ⁺: 447).

Following embodiment is according to about the illustrated step of embodiment 5, uses corresponding amine reagent synthetic.The yield percentage of reactant and M+H ⁺Be presented at parenthetic.

1,1,1-three fluoro-3-indoles-1-base-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (34%; M+H ⁺: 422);

3-(3,4-dihydro-2H-quinoxaline-1-yl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (58%; M+H ⁺: 439);

3-(3,4-dihydro-2H-quinoline-1-yl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (55%; M+H ⁺: 438); And

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-pyrrolo-[2,3-c] pyridine-1-base propan-2-ol (17%; M+H ⁺: 423).

Embodiment 7:3-(3,5-dimethoxy phenoxy group)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol

With polymer bonded 2-tertiary butyl imido grpup-2-diethylin-1,3-dimethyl perhydro-1,3-phenodiazine phospha cyclohexane (1,3,2-diazaphosphorine) (PS-BEMP) (20 milligrams, 0.040 mmole) (5 milligrams of 1-phenyl-5-(2-trifluoromethyl Oxyranyle)-1H-indazole, 0.016 mmole) with 3, the suspension vibration in the solution of 5-syringol (3 milligrams, 0.019 mmole) in THF, and be heated to 60 ℃, went through 48 hours.The filtering reaction thing removing resin, and washs with THF.Make the solution for vacuum evaporation of merging.Separate rough white solid by preparation property reversed-phase HPLC, and desired product 3-(3,5-dimethoxy phenoxy group)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol, for white solid (6 milligrams, 79% productive rate; M+H ⁺: 459).

Following embodiment is according to about the illustrated step of embodiment 7, uses corresponding phenol reagent synthetic with corresponding epoxide.Work as where applicable, the yield percentage of reactant and M+H ⁺Be presented at parenthetic.

1,1,1-three fluoro-3-phenoxy group-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (78%; M+H ⁺: 399);

3-(3,5-two fluorophenoxies)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (68%; M+H ⁺: 435);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(2-4-trifluoromethylphenopendant) propan-2-ol (M+H ⁺: 467);

3-(2-chloro-3,5-two fluorophenoxies)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 469);

3-(5-chloro-2-methylphenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 447);

3-(4-bromine phenoxy group)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 478);

1,1,1-three fluoro-3-(indane-5-base oxygen)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 439);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(2,4, the 6-Trichlorophenoxy) propan-2-ol (M+H ⁺: 501);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(2,4,6-trimethylammonium phenoxy group) propan-2-ol (M+H ⁺: 441);

3-(3-bromine phenoxy group)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 478);

3-(2,4 dichloro benzene oxygen base)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 467);

3-(2-bromine phenoxy group)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 478);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(3-4-trifluoromethylphenopendant) propan-2-ol (M+H ⁺: 467);

3-(2-chloro-5-methylphenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 447);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(4-4-trifluoromethylphenopendant) propan-2-ol (M+H ⁺: 467);

1,1,1-three fluoro-3-(naphthalene-2-base oxygen)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 449);

3-(2-chlorophenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 433);

3-(4-chlorophenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 433);

3-(2-chloro-4-methylphenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 447);

3-(4-chloro-2-fluorophenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 451);

1,1,1-three fluoro-3-(4-fluoro-2-methylphenoxy)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 431);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(2,3,4-trifluoromethoxy phenoxy base) propan-2-ol (M+H ⁺: 453);

1,1,1-three fluoro-3-(7-methoxynaphthalene-2-base oxygen)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 479);

3-(2-bromo-5-fluorophenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 496);

1,1,1-three fluoro-3-(2-fluoro-5-4-trifluoromethylphenopendant)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 485);

3-(4-bromo-3-methylphenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 492);

1,1,1-three fluoro-3-(2-fluoro-5-methylphenoxy)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 431);

1,1,1-three fluoro-3-(4-methylthio group phenoxy group)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 445);

3-(3-chlorophenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 433);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-o-tolyloxy propan-2-ol (M+H ⁺: 413);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-m-tolyloxy propan-2-ol (M+H ⁺: 413);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-p-tolyloxy propan-2-ol (M+H ⁺: 413);

3-(2, the 6-dimethyl phenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 427);

3-(2, the 6-dichlorophenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 467);

3-(3, the 5-dichlorophenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 467);

1,1,1-three fluoro-3-(naphthalene-1-base oxygen)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 449);

1,1,1-three fluoro-3-(isoquinoline 99.9-7-base oxygen)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 450);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(2-Trifluoromethyl phenyl ether oxygen base) propan-2-ol (M+H ⁺: 483);

1,1,1-three fluoro-3-(4-phenyl amino phenoxy group)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 490);

3-(3-chloro-4-methylphenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 447);

1,1,1-three fluoro-3-(3-fluoro-5-4-trifluoromethylphenopendant)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 485);

1,1,1-three fluoro-3-(2-methylthio group phenoxy group)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 445);

3-(4-chloro-3-4-trifluoromethylphenopendant)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 501);

3-(2,4-two chloro-6-methylphenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 481);

3-(2,6-two chloro-4-methylphenoxy)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 481);

3-methoxyl group-4-[3,3,3-three fluoro-2-hydroxyl-2-(1-phenyl-1H-indazole-5-yl) propoxy-] phenylformic acid ethyl ester (M+H ⁺: 501);

1,1,1-three fluoro-3-(4-imidazoles-1-phenoxyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 465);

3-(3-chloro-5-5-flumethiazine-2-base oxygen)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 502);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(5,6,7,8-naphthane-1-base oxygen) propan-2-ol (M+H ⁺: 411);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(5,6,7,8-naphthane-2-base oxygen) propan-2-ol (M+H ⁺: 471);

2-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxyl propoxy-} benzonitrile (M+H ⁺: 441);

3-(2-bromine phenoxy group)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 496);

3-(2-chlorophenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 451);

3-(2,4 dichloro benzene oxygen base)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 485);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2,4, the 6-Trichlorophenoxy) propan-2-ol (M+H ⁺: 519);

3-(2-chloro-5-methylphenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 465);

3-(2, the 6-dichlorophenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 485);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2-4-trifluoromethylphenopendant) propan-2-ol (M+H ⁺: 485);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-o-tolyloxy propan-2-ol (M+H ⁺: 431);

3-(2, the 4-dimethyl phenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 445);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2,4,6-trimethylammonium phenoxy group) propan-2-ol (M+H ⁺: 459);

3-(2, the 6-dimethyl phenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 445);

3-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxyl propoxy-} benzonitrile (M+H ⁺: 442);

3-(3-bromine phenoxy group)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 496);

1,1,1-three fluoro-3-(3-fluorophenoxy)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 435);

3-(3,5-two fluorophenoxies)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 453);

3-(3-chlorophenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 451);

3-(3, the 5-dichlorophenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 485);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-m-tolyloxy propan-2-ol (M+H ⁺: 431);

3-(3, the 5-dimethyl phenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 445);

4-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxyl propoxy-} benzonitrile (M+H ⁺: 442);

3-(4-bromine phenoxy group)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 496);

1,1,1-three fluoro-3-(4-fluorophenoxy)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 435);

3-(4-chlorophenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 451);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(4-4-trifluoromethylphenopendant) propan-2-ol (M+H ⁺: 485);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-p-tolyloxy propan-2-ol (M+H ⁺: 431);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(indane-5-base oxygen) propan-2-ol (M+H ⁺: 457);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(naphthalene-1-base oxygen) propan-2-ol (M+H ⁺: 467);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(naphthalene-2-base oxygen) propan-2-ol (M+H ⁺: 467);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(quinoline-5-base oxygen) propan-2-ol (M+H ⁺: 468);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(quinoline-8-base oxygen) propan-2-ol (M+H ⁺: 468);

3-(2,4 difluorobenzene oxygen base)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 453);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(quinoline-7-base oxygen) propan-2-ol (M+H ⁺: 468);

3-methoxyl group-4-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxyl propoxy-} phenylformic acid ethyl ester (M+H ⁺: 519);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(4-phenyl amino phenoxy group) propan-2-ol (M+H ⁺: 508);

N-(4-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxyl propoxy-} phenyl) butyramide (M+H ⁺: 502);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(4-trifluoromethylthio phenoxy group) propan-2-ol (M+H ⁺: 517);

5-ethanoyl-2-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxyl propoxy-} benzoic acid methyl ester (M+H ⁺: 517);

3-(2-bromo-5-fluorophenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 514);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2,3,4-trifluoromethoxy phenoxy base) propan-2-ol (M+H ⁺: 471);

3-(2,5-two fluorophenoxies)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 453);

3-(4-chloro-3-4-trifluoromethylphenopendant)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 519);

3-(acridine-4-base oxygen)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 518);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(3-morpholine-4-phenoxyl) propan-2-ol (M+H ⁺: 502);

2-chloro-4-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxyl propoxy-} benzonitrile (M+H ⁺: 476);

3-(4-bromo-2-methylphenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 510);

3-(3-chloro-4-methylphenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 465);

3-(5-chloro-2-methylphenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 465);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2,3,6-trifluoromethoxy phenoxy base) propan-2-ol (M+H ⁺: 471);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2,4,5-trifluoromethoxy phenoxy base) propan-2-ol (M+H ⁺: 471);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2,4,6-trifluoromethoxy phenoxy base) propan-2-ol (M+H ⁺: 471);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2-fluoro-5-4-trifluoromethylphenopendant) propan-2-ol (M+H ⁺: 503);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(3-fluoro-5-4-trifluoromethylphenopendant) propan-2-ol (M+H ⁺: 503);

3-(2-chloro-4-methylphenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 465);

3-(4-chloro-2-fluorophenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 469);

1,1,1-three fluoro-3-(4-fluoro-2-methylphenoxy)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 449);

1,1,1-three fluoro-3-(2-fluoro-6-methoxyl group phenoxy group)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 465);

3-(2-chloro-3,5-two fluorophenoxies)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 487);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2,3,5-trifluoromethoxy phenoxy base) propan-2-ol (M+H ⁺: 471);

4-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxyl propoxy-} benzonitrile (M+H ⁺: 497);

3-(4-bromo-3-methylphenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 510);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(6-methoxynaphthalene-2-base oxygen) propan-2-ol (M+H ⁺: 497);

3-(2,6-two chloro-4-methylphenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 499);

4-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxyl propoxy-} indan-1-one (M+H ⁺: 471);

5-bromo-2-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxyl propoxy-} benzonitrile (M+H ⁺: 521);

1,1,1-three fluoro-3-(2-fluoro-5-methylphenoxy)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 449);

5-chloro-2-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxyl propoxy-} benzonitrile (M+H ⁺: 476);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2-Trifluoromethyl phenyl ether oxygen base) propan-2-ol (M+H ⁺: 501);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(isoquinoline 99.9-7-base oxygen) propan-2-ol (M+H ⁺: 468);

3-(3,4-dimethoxy phenoxy group)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 477);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(3-Trifluoromethyl phenyl ether oxygen base) propan-2-ol (M+H ⁺: 501); And

3-(2,4-two chloro-6-methylphenoxy)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 499).

Embodiment 8:1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-thiophenyl propan-2-ol

To (50.0 milligrams of 1-phenyl-5-(2-trifluoromethyl Oxyranyle)-1H-indazole, 0.2 mmole) in the solution in DMF (0.5 milliliter), add benzenethiol (54.2 microlitres, 0.5 mmole), and formed mixture is heated to 120 ℃ in sealed tube, went through 14 hours.Make reaction mixture be cooled to room temperature,,,, and filter with dried over sodium sulfate with three parts of each 10 ml waters and the washing of 10 mL of saline with 5 milliliters of EtOAc dilutions.Remove solvent by rotary evaporation, and make crude material pass through rapid column chromatography purifying (with 85% hexane/EtOAc wash-out).Obtain desired product 1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-thiophenyl propan-2-ol, for water white oil (44 milligrams, 64% productive rate; M+H ⁺: 415).

Embodiment 9:1,1,1-three fluoro-3-(4-fluorophenyl sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol

1 of polystyrene will be bonded to, 5, (52 milligrams of 7-three azabicyclics [4.4.0] last of the ten Heavenly stems-5-alkene (PS-TBD), 0.134 mmole) (17 milligrams of 1-phenyl-5-(2-trifluoromethyl Oxyranyle)-1H-indazole, 0.056 mmole) with (9 milligrams in 4-fluorobenzene mercaptan, 0.070 the suspension in the solution in THF mmole) at room temperature vibrated 12 hours.Filter resin, and wash with THF.Make the solution for vacuum concentration of merging, and get white solid.The RP-HPLC that functional quality triggers makes the crude material purifying, and obtains desired product 1,1,1-three fluoro-3-(4-fluorophenyl sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol, for water white oil (20 milligrams, 86% productive rate; M+H ⁺: 433).

Following embodiment is according to about the illustrated step of embodiment 9, uses corresponding thiophenol reagent synthetic with corresponding epoxide.M+H ⁺Be presented at parenthetic.

1,1,1-three fluoro-3-(2-isopropyl benzene sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 457);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(pyridine-2-base sulfenyl) propan-2-ol (M+H ⁺: 416);

3-(4-ethylbenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol; (M+H ⁺: 443);

4-methyl-7-[3,3,3-three fluoro-2-hydroxyl-2-(1-phenyl-1H-indazole-5-yl) rosickyite base]-1-chromen-2-one (M+H ⁺: 497);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(3-trifluoromethyl thiophenyl) propan-2-ol (M+H ⁺: 483);

3-(2,3-dichlorobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 483);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(4-trifluoromethyl thiophenyl) propan-2-ol (M+H ⁺: 483);

1,1,1-three fluoro-3-(naphthalene-1-base sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 465);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(4-thiophene-2-yl pyrimidines-2-base sulfenyl) propan-2-ol (M+H ⁺: 499);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(4-phenyl pyrimidine-2-base sulfenyl) propan-2-ol (M+H ⁺: 493);

3-[4-(4-chloro-phenyl-) pyrimidine-2-base sulfenyl]-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 527);

6-methyl-2-[3,3,3-three fluoro-2-hydroxyl-2-(1-phenyl-1H-indazole-5-yl) rosickyite base]-4-trifluoromethyl nicotine nitrile (M+H ⁺: 523);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(5-5-flumethiazine-2-base sulfenyl) propan-2-ol (M+H ⁺: 484);

3-(2-chloro-4-fluorobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 467);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(4-trifluoromethoxy thiophenyl) propan-2-ol (M+H ⁺: 499);

3-(4-bromo-2-trifluoromethoxy thiophenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 578);

1,1,1-three fluoro-3-(4-anisole sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 445);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(quinoline-2-base sulfenyl) propan-2-ol (M+H ⁺: 466);

3-(4-chlorobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 449);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(pyrimidine-2-base sulfenyl) propan-2-ol (M+H ⁺: 417);

3-(4,6-dimethyl pyrimidine-2-base sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 445);

3-(3,4-dichlorobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 483);

3-(2,5-dichlorobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 483);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(pyridin-4-yl sulfenyl) propan-2-ol (M+H ⁺: 416);

1,1,1-three fluoro-3-(3-anisole sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 445);

1,1,1-three fluoro-3-(2-anisole sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 445);

3-(3-chlorobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 449);

3-(2,6-dichlorobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 483);

3-(2,6-dichlorobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 449);

3-(3-bromobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 494);

3-(3,4-dimethyl benzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 443);

1,1,1-three fluoro-3-(naphthalene-2-base sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 465);

1,1,1-three fluoro-3-(2-fluorobenzene sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 433);

1,1,1-three fluoro-3-(3-fluorobenzene sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 433);

3-(2,5-dimethoxy thiophenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 474);

3-(2,4-dimethyl benzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 443);

3-(2,5-dimethyl benzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 443);

3-(2,6-dimethyl benzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 443);

3-(2-ethylbenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 443);

2-[3,3,3-three fluoro-2-hydroxyl-2-(1-phenyl-1H-indazole-5-yl) rosickyite base] benzoic acid methyl ester (M+H ⁺: 473);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(4-trifluoromethyl pyrimidine-2-base sulfenyl) propan-2-ol (M+H ⁺: 485);

3-(3,5-dimethyl benzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 443);

3-(3,5-couple-the trifluoromethyl thiophenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 551);

3-(2,4 difluorobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 451);

1,1,1-three fluoro-3-(4-isopropyl benzene sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 457);

3-(2,4 dichloro benzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 483);

3-(3,5-dichlorobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 483);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(2-trifluoromethyl thiophenyl) propan-2-ol (M+H ⁺: 483);

3-(3,4-difluoro thiophenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 483);

3-(3-phenetole sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 459);

3-(4-tert.-butylbenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 471);

N-{4-[3,3,3-three fluoro-2-hydroxyl-2-(1-phenyl-1H-indazole-5-yl) rosickyite base] phenyl } ethanamide (M+H ⁺: 472);

3-(4-bromobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 494);

1,1,1-three fluoro-3-(4-fluorobenzene sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 433);

1,1,1-three fluoro-3-(4-nitrophenylsulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 460);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-o-tolyl sulfenyl propan-2-ol (M+H ⁺: 429);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-m-tolyl sulfenyl propan-2-ol (M+H ⁺: 429);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-p-tolyl sulfenyl propan-2-ol (M+H ⁺: 429);

3-(3-chloro-4-fluorobenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 467);

3-(3,4-dimethoxy thiophenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 475);

3-(the 5-tertiary butyl-2-methylbenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 485);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(2,4,6-Three methyl Benzene sulfenyl) propan-2-ol (M+H ⁺: 457);

1,1,1-three fluoro-3-(4-methylthio phenyl sulfenyl)-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 461);

3-(2-chloro-6-methylbenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 463);

3-(2-tert.-butylbenzene sulfenyl)-1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol (M+H ⁺: 471);

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(3-5-flumethiazine-2-base sulfenyl) propan-2-ol (M+H ⁺: 484); And

1,1,1-three fluoro-2-(1-phenyl-1H-indazole-5-yl)-3-(3-trifluoromethoxy thiophenyl) propan-2-ol (M+H ⁺: 499).

Embodiment 10:1,1,1-three fluoro-2-phenyl-3-(1-phenyl-1H-indazole-5-yl) propan-2-ol

Step (a): in 50 ml flasks, place the 1-trimethyl silyl-1 among 8 milliliters of THF, 3-dithian (4.0 equivalent).Make this solution be cooled to-78 ℃, and dropping n-BuLi (2.5M, in hexane, 3.0 equivalents).After having added, make reactant be warmed to 0 ℃, and it was stirred 15 minutes.In this section period, make the solution cooling return back to-78 ℃, and add the 1-phenyl-solution of 1H-indazole-5-formaldehyde (384 milligrams, 1 equivalent) in 4 milliliters of THF, and reactant is stirred down in-78 ℃, went through 30 minutes.Reaction mixture is diluted with 20 ml waters, and with two parts of each 50 milliliters of EtOAc extractions.The organic substance that makes merging filters with dried over sodium sulfate, and vacuum-evaporation.Make residue pass through the flash chromatography purifying,, be light color oil (91% productive rate, M+H so that 5-(1,3-dithian-2-ylidenylmethyl)-1-phenyl-1H-indazole to be provided ⁺: 325).

Step (b): in 50 ml flasks, place 8 milliliters of CH ₂Cl ₂In 5-(1,3-dithian-2-ylidenylmethyl)-1-phenyl-1H-indazole (511 milligrams, 1 equivalent).In this solution, add triethyl-silicane (0.8 milliliter, 3.2 equivalents), then be trifluoroacetic acid (0.32 milliliter, 2.6 equivalents).This solution was at room temperature stirred 18 hours.In reactant, slowly add 20 milliliters of saturated sodium bicarbonate solutions.It is transferred to separating funnel, and with two parts of each 50 milliliters of CH ₂Cl ₂Extraction.Make organic grade of part drying, filter, and vacuum-evaporation.Make residue adhere to silica gel, and by the flash chromatography purifying,, be light yellow oil so that 5-(1,3-dithian-2-ylmethyl)-1-phenyl-1H-indazole to be provided, its be when leaving standstill, solidify (437 milligrams, 85% productive rate, M+H ⁺: 327).

Step (c): in 5-(1,3-dithian-2-the ylmethyl)-solution of 1-phenyl-1H-indazole (437 milligrams, 1 equivalent) in 50 milliliters of acetonitriles and 15 ml waters, add methyl iodide (9.8 milliliters, 50 equivalents).Reactant is at room temperature stirred.After 4 hours, reactant is poured in the separating funnel, and with 200 milliliters of CH ₂Cl ₂With 100 milliliters of saturated sodium bicarbonate solution dilutions.Vacuum is removed organic grade of part, and with CH ₂Cl ₂Aqueous solution extraction.Make organic grade of part drying of merging, filter, and vacuum-evaporation.Make residue pass through the flash chromatography purifying.Merge desired wash-out level part, and vacuum-evaporation, so that (1-phenyl-1H-indazole-5-yl) acetaldehyde to be provided, for water white oil (277 milligrams, 38% productive rate, M+H ⁺: 237).

Step (d): under 0 ℃, in 20 milliliters little glass bottles, place (1-phenyl-1H-indazole-5-yl) acetaldehyde (50 milligrams, 1.0 equivalents) among 2 milliliters of THF.To wherein adding phenyl-magnesium-bromide (1.0M, in THF, 0.64 milliliter, 3.0 equivalents), and make reactant be warmed to ambient temperature overnight (18 hours).Make reaction mixture be cooled to 0 ℃, and make the stopping of reaction with 1 milliliter of saturated aqueous ammonium chloride.With three parts of each 10 milliliters of EtOAc aqueous layer extracted, and with the organic layer merging, and with dried over sodium sulfate, filter, and vacuum evaporating solvent.Make crude material pass through the flash chromatography purifying, so that 1-phenyl-2-(1-phenyl-1H-indazole-5-yl) to be provided ethanol, for white solid (24 milligrams, 36% productive rate, M+H ⁺: 315).

Step (e): in 100 ml flasks, place 10 milliliters of CH ₂Cl ₂In 1-phenyl-2-(1-phenyl-1H-indazole-5-yl) ethanol (143 milligrams, 1 equivalent).In this solution, add Dess-MartinShi periodinane (193 milligrams, 1 equivalent), and reactant is at room temperature stirred.After 30 minutes, with mixture with CH ₂Cl ₂Dilute, and wash with saturated sodium bicarbonate solution.Make the organic substance drying, filter, and vacuum-evaporation.Make residue pass through the flash chromatography purifying.Merge desired wash-out level part, and vacuum-evaporation, so that 1-phenyl-2-(1-phenyl-1H-indazole-5-yl) to be provided ethyl ketone, for white solid (124 milligrams, 87% productive rate, M+H ⁺: 313).

Step (f): in 100 ml flasks, place 1-phenyl-2-(1-phenyl-1H-indazole-5-yl) ethyl ketone (100 milligrams, 1 equivalent) among 5 milliliters of THF.Make it be cooled to 0 ℃, to wherein adding trifluoromethyl trimethyl silyl (0.08 milliliter, 1.6 equivalents).After 30 minutes, make reactant be warmed to room temperature, and drip tetrabutylammonium (TBAF) (0.51 milliliter, 1.6 equivalents).After 20 minutes, reactant is diluted with methyl alcohol, and vacuum-evaporation.Make residue pass through the flash chromatography purifying, desired product 1,1 be provided, 1-three fluoro-2-phenyl-3-(1-phenyl-1H-indazole-5-yl) propan-2-ol, for white solid (21 milligrams, 20% productive rate, M+H ⁺: 383).

Embodiment 11:2,2,2-three fluoro-1-phenyl-1-(1-phenyl-1H-benzotriazole-5-yl) ethanol

Step (a): in the solution of (4-chloro-3-nitrophenyl) phenyl ketone (1.9 grams, 7.26 mmoles) in DMF, add aniline (1.9 milliliters, 20.85 mmoles) and HunigShi alkali (3.64 milliliters, 20.91 mmoles).Formed filbert solution is heated to 100 ℃, went through 12 hours.Make solution be cooled to room temperature, and incline example at leisure on 100 milliliters of cold water, to produce throw out.Collect product (3-nitro-4-phenyl amino phenyl) phenyl ketone by filtering, then,, be yellow solid (5.0 grams, 75% productive rate, M+H from alcohol crystal ⁺: 319).

Step (b): in the slurries in 10 milliliters of EtOH and the 6 milliliters of acetate, add iron powder (3.5 restrain 62.84 mmoles) to (3-nitro-4-phenyl amino phenyl) phenyl ketone (1.0 gram, 3.14 mmoles).Black mixture is heated to 90 ℃ to be gone through 2 hours.Make dark red solution through CELITE The flocculating aids pad filters, and washes with EtOAc, and neutralizes with saturated sodium bicarbonate solution.With organic layer Yi Shui, salt water washing, with dried over sodium sulfate, filter, and vacuum evaporating solvent, and product (3-amino-4-phenyl amino phenyl) phenyl ketone, be yellow solid, its do not need purifying (850 milligrams, 94% productive rate, M+H ⁺: 289).

Step (c): in the pre-cooled solution of (3-amino-4-phenyl amino phenyl) phenyl ketone (400 milligrams, 1.39 mmoles) in 28 milliliters of AcOH, Sodium Nitrite (145 milligrams, 2.08 mmoles) is added in gradation, goes through 10 minutes, and stirs.After 30 minutes, add frozen water, and desired product phenyl-(1-phenyl-1H-benzotriazole-5-yl) ketone precipitation, be the tawny solid, with its filtration, and with water washing.Making the dry liquid of crossing of product, is the tawny solid with the acquisition, its do not need purifying (400 milligrams, 96% productive rate, M+H ⁺: 300).

Step (d): under 0 ℃, in the phenyl-pre-cooled solution of (1-phenyl-1H-benzotriazole-5-yl) ketone (80 milligrams, 0.27 mmole) in THF, drip TMSCF ₃Formed yellow solution was stirred 15 minutes down at 0 ℃, then, under 0 ℃, the solution of dropping tetrabutylammonium (TBAF) (1M, in THF, 0.2 milliliter, 0.2 mmole).Reaction mixture was at room temperature stirred 12 hours.Vacuum-evaporation THF, and oil residues is dissolved among the EtOAc, then, Yi Shui and salt water washing.Make crude material pass through quick purification by silica gel column chromatography (with 95%-85% hexane/EtOAc wash-out).Obtain desired product 2,2,2-three fluoro-1-phenyl-1-(1-phenyl-1H-benzotriazole-5-yl) ethanol, for tawny foam thing (32 milligrams, 32% productive rate, M+H ⁺: 370).

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-benzotriazole-5-yl]-the 1-phenylethyl alcohol (59%, M+H ⁺: be to begin 389), and according to about embodiment 11 step a), b with the 4-fluoroaniline), c) and d) illustrated step preparation.

Embodiment 12:2,2,2-three fluoro-1-phenyl-1-(1-phenyl-1H-benzoglyoxaline-5-yl) ethanol

Step (a): the phenyl-solution of (1-phenyl-1H-benzotriazole-5-yl) ketone (deriving from embodiment 10) trimethyl orthoformate in methyl alcohol is heated to backflow.Make reaction mixture be cooled to room temperature.Make methyl alcohol vacuum-evaporation, and desired phenyl-(1-phenyl-1H-benzoglyoxaline-5-yl) ketone is passed through quick purification by silica gel column chromatography.

Step (b): under 0 ℃, in phenyl-(1-phenyl-1H-benzoglyoxaline-5-yl) ketone pre-cooled solution in THF, drip TMSCF ₃Formed yellow solution is stirred down at 0 ℃, and under 0 ℃, drip the solution of tetrabutylammonium (TBAF).Reaction mixture is at room temperature stirred.Make THF vacuum-evaporation, and oil residues is dissolved among the EtOAc, then, Yi Shui and salt water washing.With desired product 2,2,2-three fluoro-1-phenyl-1-(1-phenyl-1H-benzoglyoxaline-5-yl) ethanol is by quick purification by silica gel column chromatography.

Embodiment 13: cyclopropyl phenyl-(1-phenyl-1H-indazole-5-yl) methyl alcohol

Step (a): at-78 ℃, in the solution of 1-phenyl-1H-indazole-5-nitrile (1.23 grams, 5.6 mmoles) in 20.0 milliliters of THF, interpolation cyclopropyl bromination magnesium (33.7 milliliters, 0.5M).Make solution be warmed to room temperature, stirred then 14 hours.Make reactant be cooled to 0 ℃, then,, make the stopping of reaction by adding 20.0 milliliters of saturated aqueous ammonium chlorides.With three parts of each 30 milliliters of EtOAc aqueous layer extracted, and,, filter with dried over sodium sulfate with the organic layer Yi Shui, the salt water washing that merge, and vacuum evaporating solvent.Obtain desired product cyclopropyl-(1-phenyl-1H-indazole-5-yl) ketone, be yellow oil, then, use EtOAc/ hexane (15%) chromatography (1.22 grams, 83% productive rate, M+H ⁺: 263).

Step (b): under 0 ℃, in the solution of cyclopropyl-(1-phenyl-1H-indazole-5-yl) ketone (0.05 gram, 0.19 mmole) in THF (0.5 milliliter), the interpolation phenyl-magnesium-bromide (1M, in THF, 0.67 milliliter, 0.67 mmole).Formed solution was at room temperature stirred 12 hours.Make reaction mixture be cooled to 0 ℃, and, make the stopping of reaction with 1 milliliter of saturated aqueous ammonium chloride.With three parts of each EtOAc aqueous layer extracted of 10 milliliters, and merge organic layer, and, filter with dried over sodium sulfate, and vacuum evaporating solvent.Obtain desired product cyclopropyl phenyl-(1-phenyl-1H-indazole-5-yl) methyl alcohol, be the white foam thing, then with silica gel column chromatography (with EtOAc/ hexane (15%) wash-out (50 milligrams, 65% productive rate; M+H ⁺: 341).

Following embodiment is according to about the illustrated step of embodiment 6 step b), uses the refined reagent of corresponding Green synthetic.The yield percentage of reactant and M+H ⁺Be presented at parenthetic.

Cyclopropyl-(3, the 5-dichlorophenyl)-(1-phenyl-1H-indazole-5-yl) methyl alcohol (32%, M+H ⁺: 410);

1-cyclopropyl-2-(3, the 5-dichlorophenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol (50%, M+H ⁺: 424);

1-cyclopropyl-1-(1-phenyl-1H-indazole-5-yl)-2-m-tolyl ethanol (31%, M+H ⁺: 369); And

1-cyclopropyl-1-(1-phenyl-1H-indazole-5-yl)-2-p-tolyl ethanol (28%, M+H ⁺: 369).

Embodiment 14:2-phenyl-1-(1-phenyl-1H-indazole-5-yl) propan-2-ol

Step (a): in 1-phenyl-2-(1-phenyl-1H-indazole-5-yl) solution of ethyl ketone in THF, add the solution (1.2 equivalent) of methylmagnesium-bromide in THF.Make reaction mixture be cooled to 0 ℃, and, make the stopping of reaction with 1 milliliter of saturated aqueous ammonium chloride.With the EtOAc aqueous layer extracted, and merge organic layer, and, filter with dried over sodium sulfate, and vacuum evaporating solvent.Make crude material pass through the flash chromatography purifying, desired product 2-phenyl-1-(1-phenyl-1H-indazole-5-yl) is provided propan-2-ol.

Embodiment 15:1-cyclopropyl-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-phenyl amino ethanol

Step (a): to iodate trimethylammonium sulphur

In the suspension in DMSO, add NaH (1.05 equivalent).Formed solution is stirred under room temperature and argon atmosphere.The solution of this ylide compound is added into cyclopropyl-1-[1-(4-fluorophenyl)-1 H-indazole-5-yl] in the solution of ketone (0.9 equivalent) in DMSO, and formed solution at room temperature stirred.Reaction mixture is poured over waterborne, and extracts with EtOAc.The organic layer that merges with the salt water washing, with dried over sodium sulfate, is filtered, and vacuum evaporating solvent.Make crude material pass through the rapid column chromatography purifying, to obtain desired product 5-(2-cyclopropyl rings oxirane group)-1-(4-fluorophenyl)-1H-indazole.

Step (b): in the solution of aniline in DMF, add NaH (1 equivalent).In this solution, add 5-(2-cyclopropyl rings oxirane group)-1-(4-fluorophenyl)-1H-indazole.Formed solution is heated to 80 ℃.Make reaction mixture be cooled to room temperature, then,, make the stopping of reaction with saturated ammonium chloride solution.Add ethyl acetate, and with organic layer with the salt water washing, with dried over mgso, and filter.Vacuum evaporating solvent, and make crude material pass through the rapid column chromatography purifying, to obtain desired product 1-cyclopropyl-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-phenyl amino ethanol.

Embodiment 16:1-cyclopropyl-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-thiophenyl ethanol

Thiophenol and 5-(2-cyclopropyl rings oxirane group)-1-(4-the fluorophenyl)-solution of 1H-indazole in DMF are heated to 80 ℃.Make reaction mixture be cooled to room temperature, then,, make the stopping of reaction with saturated ammonium chloride solution.Add ethyl acetate, and with organic layer with the salt water washing, with dried over mgso, and filter.Vacuum evaporating solvent, and make crude material pass through the rapid column chromatography purifying, to obtain desired product 1-cyclopropyl-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-thiophenyl ethanol.

Embodiment 17:1-cyclopropyl-2-(3,5-two fluorophenoxies)-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol

1 of polystyrene will be bonded to, 5, (52 milligrams of 7-three azabicyclos [4.4.0] last of the ten Heavenly stems-5-alkene (PS-TBD), 0.134 mmole) at 5-(2-cyclopropyl rings oxirane group)-1-(4-fluorophenyl)-1H-indazole (0.5 equivalent) and 3, the suspension in the solution of 5-difluorophenol (1.0 equivalent) in THF at room temperature vibrates.Filter resin, and wash with THF.Make the solution for vacuum concentration of merging, and make crude material pass through the rapid column chromatography purifying, to obtain desired product cyclopropyl-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-thiophenyl ethanol.

Embodiment 18: cyclopropyl phenyl-(1-phenyl-1H-benzotriazole-5-yl) methyl alcohol

In the phenyl-solution of (1-phenyl-1H-benzotriazole-5-yl) ketone (70 milligrams, 0.23 mmole) in THF, interpolation cyclopropyl bromination magnesium (0.5M, in THF, 0.8 milliliter, 0.40 mmole).Formed brown solution was at room temperature stirred 6 hours.With 2 milliliters of saturated aqueous ammonium chlorides, make the stopping of reaction, with the EtOAc dilution, and extraction.With organic layer Yi Shui and salt water washing, with sal epsom (MgSO ₄) drying, then, filter, and vacuum-evaporation.Make crude material pass through rapid column chromatography purifying (with 95%-85% hexane/EtOAc wash-out), obtaining desired product cyclopropyl phenyl-1-(1-phenyl-1H-benzotriazole-5-yl) methyl alcohol, for pale solid (33 milligrams, 41%, M+H ⁺: 342).

Embodiment 19: cyclopropyl-[1-(4-fluorophenyl)-1H-benzotriazole-5-yl] phenyl methanol

In the solution of [1-(4-fluorophenyl)-1H-benzotriazole-5-yl] phenyl ketone (107 milligrams, 0.34 mmole) in THF, interpolation cyclopropyl bromination magnesium (0.5M, in THF, 1.5 milliliters, 0.75 mmole).Formed brown solution was at room temperature stirred 6 hours.With 2 milliliters of saturated aqueous ammonium chlorides, make the stopping of reaction, with the EtOAc dilution, and extraction.With organic layer Yi Shui and salt water washing, with dried over mgso, then, filter, and vacuum-evaporation.Make crude material pass through rapid column chromatography purifying (with 95%-85% hexane/EtOAc wash-out), obtaining desired product cyclopropyl-[1-(4-fluorophenyl)-1H-benzotriazole-5-yl] phenyl methanol, for pale solid (70 milligrams, 57%, M+H ⁺: 360).

Embodiment 20: cyclopropyl phenyl-(1-phenyl-1H-indoles-5-yl) methyl alcohol

Step (a): under-78 ℃, in the 1-phenyl-1H-indoles-solution of 5-nitrile in THF, add basic magnesium bromide (1.2 equivalent) in the ring.This solution is warmed to room temperature.Make reactant be cooled to 0 ℃, then,, make the stopping of reaction by adding saturated aqueous ammonium chloride.With the EtOAc aqueous layer extracted, and,, filter with dried over sodium sulfate with the organic layer Yi Shui, the salt water washing that merge, and vacuum evaporating solvent.Obtain desired product cyclopropyl-(1-phenyl-1H-indoles-5-yl) ketone, then, pass through column chromatography purification.

Step (b): under 0 ℃, in cyclopropyl-(1-phenyl-1H-indoles-5-yl) ketone solution in THF, add phenyl-magnesium-bromide (1.3 equivalent).Formed solution is at room temperature stirred.Make reaction mixture be cooled to 0 ℃, and, make the stopping of reaction with saturated aqueous ammonium chloride.With the EtOAc aqueous layer extracted, and merge organic layer, and, filter with dried over sodium sulfate, and vacuum evaporating solvent.Obtain desired product cyclopropyl phenyl-(1-phenyl-1H-indoles-5-yl) methyl alcohol, then, use silica gel column chromatography.

Embodiment 21:1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-indoles-1-base propan-2-ol

1-(4-fluorophenyl)-5-(2-trifluoromethyl the Oxyranyle)-solution of 1H-indazole (24 milligrams, 0.075 mmole) in 500 microlitre DMSO is added in the indoles (0.090 mmole).With mixture vibration 15 minutes,, then, add the solution (90 microlitres, the 1M solution in THF, 0.090 mmole) of hexamethyl dimethyl silanyl nitrogen base sodium (NaHMDS), and formed mixture was at room temperature vibrated 16 hours with the dissolving indoles.Make the stopping of reaction by adding 50 microliters of water, then, vibrate after 30 minutes, make mixture through CELITE

Flocculating aids filters.With two parts of little glass bottles of each 300 microlitre DMSO flushing reaction, and make it pass through CELITE

Flocculating aids.At last, with two parts of each 200 microlitre DMSO washing CELITE

Filter cake.Make the solution for vacuum evaporation of merging.Make crude product by preparation property reversed-phase HPLC purifying, and get desired product (M+H ⁺: 440).

Following embodiment is according to about the illustrated step of embodiment 21, uses corresponding indoles reagent synthetic with corresponding epoxide.M+H ⁺Be presented at parenthetic.

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(4-skatole-1-yl) propan-2-ol (M+H ⁺: 454);

3-[2-(4-chloro-phenyl-) indoles-1-yl]-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 550);

(1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-the 1H-indol-3-yl) acetonitrile (M+H ⁺: 479);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(6-methoxyl group indoles-1-yl) propan-2-ol (M+H ⁺: 470);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(5-skatole-1-yl) propan-2-ol (M+H ⁺: 454);

3-(4-benzyloxy indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 546);

3-(4-chloro-indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 474);

3-(6-chloro-indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 474);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(6-skatole-1-yl) propan-2-ol (M+H ⁺: 454);

1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-1H-indoles-4-formic acid methyl ester (M+H ⁺: 498);

1,1,1-three fluoro-3-(6-fluoro indole-1-yl)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 458);

1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-1H-indole-3-carboxylic acid methyl ester (M+H ⁺: 498);

2,2,2-three fluoro-1-(1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-the 1H-indol-3-yl) ethyl ketone (M+H ⁺: 536);

1,1,1-three fluoro-3-(4-fluoro indole-1-yl)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 458);

N-[2-(5-methoxyl group-1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-the 1H-indol-3-yl) ethyl] ethanamide (M+H ⁺: 555);

3-(7-bromo indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 519);

3-(7-chloro-indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 474);

(the 2-methyl isophthalic acid-3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-the 1H-indol-3-yl) acetate ethyl ester (M+H ⁺: 540);

1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-1H-indole-5-carboxylic acid methyl ester (M+H ⁺: 498);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2-methyl-5-nitro indoles-1-yl) propan-2-ol (M+H ⁺: 499);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-[2-(4-fluorophenyl) indoles-1-yl] propan-2-ol (M+H ⁺: 534);

3-(4-bromo indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 519);

3-(6-bromo indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 519);

3-(3-dimethylaminomethyl-6-methoxyl group indoles-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 527);

(5-methoxyl group-1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-the 1H-indol-3-yl) acetonitrile (M+H ⁺: 509);

(5-benzyloxy-1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-the 1H-indol-3-yl) acetonitrile (M+H ⁺: 585);

1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-1H-indoles-6-formic acid methyl ester (M+H ⁺: 498);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(7-nitroindoline-1-yl) propan-2-ol (M+H ⁺: 485);

1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-1H-indoles-4-nitrile (M+H ⁺: 465);

3-(5-benzyloxy indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 546);

1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-1H-indoles-5-nitrile (M+H ⁺: 465);

3-(3-dimethylaminomethyl-5-methoxyl group indoles-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 527);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(5-methoxyl group-2 methyl indole-1-yl) propan-2-ol (M+H ⁺: 484);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2 methyl indole-1-yl) propan-2-ol (M+H ⁺: 454);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(3-skatole-1-yl) propan-2-ol (M+H ⁺: 454);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(7-skatole-1-yl) propan-2-ol (M+H ⁺: 454);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(5-nitroindoline-1-yl) propan-2-ol (M+H ⁺: 485);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2-phenylindone-1-yl) propan-2-ol (M+H ⁺: 516);

(2-phenyl-1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-the 1H-indol-3-yl) acetonitrile (M+H ⁺: 554);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-pyrrolo-[2,3-c] pyridine-1-base propan-2-ol (M+H ⁺: 441);

3-(7-ethylindole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 468);

3-(2,3-dimethyl-5-nitroindoline-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 513);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(6-trifluoro methyl indole-1-yl) propan-2-ol (M+H ⁺: 508);

1,1,1-three fluoro-3-(7-fluoro indole-1-yl)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 458);

1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-1H-indole-6-carbonitrile (M+H ⁺: 465);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-indoles-1-base propan-2-ol (M+H ⁺: 440);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-pyrrolo-[2,3-b] pyridine-1-base propan-2-ol (M+H ⁺: 441);

1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-1H-indole-2-carboxylic acid ethyl ester (M+H ⁺: 512);

3-(2,3-dimethyl indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 468);

1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-1H-indoles-3-nitrile (M+H ⁺: 465);

1-(1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-the 1H-indol-3-yl) ethyl ketone (M+H ⁺: 482);

3-(3-dimethylaminomethyl indoles-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 497);

(1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-the 1H-indol-3-yl) acetate ethyl ester (M+H ⁺: 526);

2-(1-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-the 1H-indol-3-yl) ethanamide (M+H ⁺: 497);

3-(5-bromo indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 519);

1,1,1-three fluoro-3-(5-fluoro indole-1-yl)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 458);

3-(5-chloro-indole-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 474);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(5-methoxyl group indoles-1-yl) propan-2-ol (M+H ⁺: 470);

3-(5,6-dimethoxy indoles-1-yl)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 500);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(4-nitroindoline-1-yl) propan-2-ol (M+H ⁺: 485); And

The 5-methyl isophthalic acid-3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 2-hydroxypropyl }-1H-indole-2-carboxylic acid ethyl ester (M+H ⁺: 485).

Embodiment 22:1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-phenyl amino propan-2-ol

1-(4-fluorophenyl)-5-(2-trifluoromethyl the Oxyranyle)-solution of 1H-indazole (24 milligrams, 0.075 mmole) in 500 microliter methanol is added in the aniline (0.090 mmole).Mixture was heated 16 hours down at 50 ℃.Make the solution for vacuum evaporation.Make crude product by preparation property reversed-phase HPLC purifying, and get desired product (M+H ⁺: 416).

Following embodiment is according to about the illustrated step of embodiment 22, uses corresponding aniline reagent synthetic with corresponding epoxide.M+H ⁺Be presented at parenthetic.

6-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxypropyl amino }-3H-isobenzofuran-1-ketone (M+H ⁺: 472);

N-(4-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxypropyl amino } phenyl) ethanamide (M+H ⁺: 473);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(indane-5-base is amino) propan-2-ol (M+H ⁺: 456);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(indane-4-base is amino) propan-2-ol (M+H ⁺: 456);

3-(3-bromophenyl amino)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 495);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the amino propan-2-ol (M+H of 3-o-tolyl ⁺: 430);

3-(4-chloro-phenyl-amino)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 450);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the amino propan-2-ol (M+H of 3-m-tolyl ⁺: 430);

3-(4-chloronaphthalene-1-base is amino)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 500);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(6-methoxypyridine-3-base is amino) propan-2-ol (M+H ⁺: 447);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(5,6,7,8-naphthane-1-base is amino) propan-2-ol (M+H ⁺: 470);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2-p-methoxy-phenyl amino) propan-2-ol (M+H ⁺: 446);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(3-p-methoxy-phenyl amino) propan-2-ol (M+H ⁺: 446);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(4-p-methoxy-phenyl amino) propan-2-ol (M+H ⁺: 446);

3-(3-chloro-phenyl-amino)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 450);

3-(5-chloro-2-aminomethyl phenyl amino)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 464);

3-(2,6-3,5-dimethylphenyl amino)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 444);

1,1,1-three fluoro-3-(4-fluorophenyl amino)-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 434);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(4-methylthio group phenyl amino) propan-2-ol (M+H ⁺: 462);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(naphthalene-2-base is amino) propan-2-ol (M+H ⁺: 466);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2-toluquinoline-8-base is amino) propan-2-ol (M+H ⁺: 481);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(aminomethyl phenyl amino) propan-2-ol (M+H ⁺: 430);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 3-[(4-p-methoxy-phenyl) methylamino] propan-2-ol (M+H ⁺: 460);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(naphthalene-1-base is amino) propan-2-ol (M+H ⁺: 466);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(4-morpholine-4-base phenyl amino) propan-2-ol (M+H ⁺: 501);

3-(2,3-dihydro-1,4-benzo dioxine-6-base is amino)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 474);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2,4,6-trifluorophenyl amino) propan-2-ol (M+H ⁺: 470);

3-(biphenyl-2-base is amino)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 492);

3-(2,4-3,5-dimethylphenyl amino)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 444);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2,4,6-trimethylphenyl amino) propan-2-ol (M+H ⁺: 444);

3-(2-ethyl-6-aminomethyl phenyl amino)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 458);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(3-methylthio group phenyl amino) propan-2-ol (M+H ⁺: 462);

3-(3,5-3,5-dimethylphenyl amino)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 444);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(4-Phenoxyphenyl amino) propan-2-ol (M+H ⁺: 508);

3-(2,4-Dimethoxyphenyl amino)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 476);

3-(3,5-Dimethoxyphenyl amino)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 476);

3-(4,5-dimethoxy-2-aminomethyl phenyl amino)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 490);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(3-Trifluoromethoxyphen-l amino) propan-2-ol (M+H ⁺: 500);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2-methoxyl group-5-trifluoromethyl amino) propan-2-ol (M+H ⁺: 514);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(4-methoxyl group-3-trifluoromethyl amino) propan-2-ol (M+H ⁺: 514);

3-(biphenyl-3-base is amino)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 492);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(4-piperidines-1-base phenyl amino) propan-2-ol (M+H ⁺: 499);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(3- Azoles--5-base phenyl amino) propan-2-ol (M+H ⁺: 483);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(4-pyridin-4-yl aminomethyl phenyl amino) propan-2-ol (M+H ⁺: 507);

3-(4-chloro-2,6-3,5-dimethylphenyl amino)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 478);

1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-3-(2-methylnaphthalene-1-base is amino) propan-2-ol (M+H ⁺: 480);

3-(biphenyl-4-base is amino)-1,1,1-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl] propan-2-ol (M+H ⁺: 492); And

5-{3,3,3-three fluoro-2-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-hydroxypropyl amino }-1,3-dihydrobenzo imidazoles-2-ketone (M+H ⁺: 472).

Embodiment 23:1-(1-allyl group-1H-indoles-4-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol

Step (a): in 100 ml flasks, place the gram of 3.0 among 15 milliliters of DMF (25.7 mmoles, 1 equivalent) indoles.Make it be cooled to 0 ℃, add 65% suspensoid of 1.5 gram (38.4 mmoles, 1.5 equivalents) sodium hydrides in Dormant oils to gradation wherein.Disengage back (30 minutes) at gas, add 3-bromopropylene (2.4 milliliters, 28.2 mmoles, 1.1 equivalents), and make reactant be warmed to room temperature.After 30 minutes, reactant is poured in 300 ml waters, and with ether (Et ₂O) extraction.Make the ether extract drying of merging, filter, and vacuum-evaporation, and be used in the next step, need not to be further purified.

Step (b): in 100 ml flasks, place the rough 1-allyl group indoles of the gram of 4 among 30 milliliters of DMF.Make it be cooled to 0 ℃, to wherein adding trifluoroacetic anhydride (5.7 milliliters, 40.7 mmoles), and reactant is at room temperature stirred.After 30 minutes, reactant is poured in the separating funnel, and diluted with ether.Separation of organic substances, and with two parts of salt solution and saturated sodium bicarbonate solution flushing.Make the organism drying, filter, and vacuum-evaporation.Make residue pass through flash chromatography purifying (0%-5%EtOAc-hexane), with provide 5.54 the gram desired product, for yellow oil (86%, M+H ⁺: 254).

Step (c): under argon gas, in 50 ml flasks, place the 1-(1-allyl group-1H-indol-3-yl)-2,2 among 10 milliliters of THF, 2-trifluoro ethyl ketone (747 milligrams, 2.6 mmoles, 1.3 equivalents).Make it be cooled to-78 ℃.In another little glass bottle, place the 1-allyl group-3-trifluoromethyl carbonyl indoles (500 milligrams, 2.0 mmoles, 1 equivalent) among 5 milliliters of THF, and make it be cooled to-78 ℃.At this moment, rapidly and drip n-BuLi (0.87 milliliter, 2.2 mmoles, 1.1 equivalent, 2.5M, in hexane) to contain bromo-indazole (according to make by steps that the people reported such as Bamborough (WO 2005/073189, its be in view of the above and for reference in this paper)) flask in.After having added, contain the solution of indoles with interpolation.After 5 minutes, with 5 ml waters, make the stopping of reaction, and be warming up to room temperature.It is diluted with EtOAc, and with water/normal saline washing.Make the organism drying, filter, and vacuum-evaporation.Make residue pass through flash chromatography purifying (0-20%EtOAc-hexane), so that 813 milligrams of desired products to be provided, for the weak yellow foam thing (88%, M+H ⁺: 466).

Following embodiment is according to about the illustrated step of embodiment 23 steps (c), uses the corresponding bromo-indazole and (indol-3-yl)-2,2 of functional groupization suitably, and 2-trifluoro ethyl ketone synthesizes.Its % productive rate and M+H ⁺Be presented at parenthetic.

1-(7-bromo-1-Methyl-1H-indole-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (44%, M+H ⁺: 519);

1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-formic acid methyl ester (48%; M+H ⁺: 498);

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-methyl-7-nitro-1H-indol-3-yl) ethanol (23%, M+H ⁺: 485);

1-(1-allyl group-1H-indol-3-yl)-2,2, and 2-three fluoro-1-(1-p-tolyl-1H-indazole-5-yl) ethanol (60%, M+H ⁺: 462);

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-Methyl-1H-indole-3-yl) ethanol (11%, M+H ⁺: 440);

1-(6-bromo-1-Methyl-1H-indole-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (15%, M+H ⁺: 519);

1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-the 1H-indole-6-carbonitrile (7%, M+H ⁺: 465);

1-benzyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-formic acid methyl ester (53%, M+H ⁺: 574); And

1-[6-bromo-1-(4-methoxy-benzyl)-1H-indol-3-yl]-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (3 1%, M+H ⁺: 625).

Embodiment 24:2-(3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl } indoles-1-yl) ethanamide

Step (a): in 50 ml flasks, place the 1-(1-allyl group-1H-indol-3-yl)-2,2 in 10 milliliters of acetone (3: 1), 2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (250 milligrams, 0.54 mmole, 1 equivalent).Make it be cooled to 0 ℃, to wherein adding potassium permanganate (KMnO with the drips of solution in 10 milliliters of acetone (3: 1) ₄94 milligrams, 0.59 mmole, 1.1 equivalents).Then, remove ice bath, and reactant was at room temperature stirred 2 hours.The filtering reaction thing, and remove volatile matter.Then, residue is made allocation process between water and EtOAc.Make the organic substance drying, filter, and vacuum-evaporation.Residue is dissolved among the minimum DMF, and by HPLC purifying (5-100%, acetonitrile/water/0.1%TFA), so that 218 milligrams of desired product 3-(3-{2 to be provided, 2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl } indoles-1-yl) propane-1, the 2-glycol, for white solid (80%, M+H ⁺: 500).

Step (b): in 50 ml flasks, place the glycol (350 milligrams, 0.70 mmole, 1 equivalent) in 6 milliliters of acetone and 2 ml waters.To wherein adding sodium periodate (172 milligrams, 0.77 mmole, 1.1 equivalents), and reactant was at room temperature stirred 72 hours.Cross filter solid, and with acetone rinsing.Then, remove volatile matter, and then mixture is transferred to separating funnel, alkalize with the aqueous solution with saturated sodium bicarbonate, and extract with EtOAc.Make the organic substance drying of merging, filter, and vacuum-evaporation, so that 319 milligrams of desired products to be provided, for the white foam thing (97%, M+H ⁺: 468).

Step (c): in 100 ml flasks, place 9 milliliters of 3: 1 acetone: the aldehyde in the water (269 milligrams, 0.58 mmole, 1 equivalent).Add potassium permanganate (100 milligrams, 0.63 mmole, 1.1 equivalents), and reactant was at room temperature stirred 2 hours.Cross filter solid, and with acetone rinsing.Remove volatile matter, and the aqueous solution is transferred to separating funnel.With EtOAc extraction water solution.Make the organic substance drying of merging, filter, and vacuum-evaporation, so that 261 milligrams of desired acid to be provided, for the tawny solid (94%, M+H ⁺: 484).

Step (d): in 7 milliliters little glass bottles, place the carboxylic acid (40 milligrams, 0.083 mmole, 1 equivalent) among 1 milliliter of DMF.To wherein adding triethylamine (63 microlitres, 0.5 mmole, 6 equivalents), then be phosphofluoric acid benzotriazole-1-base oxygen base) tripyrrole pyridine base phosphorus

(PyBOP; (56 milligrams, 0.11 mmole, 1.3 equivalents).After 5 minutes, add ammonium chloride (44 milligrams, 0.83 mmole, 10 equivalents), reactant is added a cover, and reactant was at room temperature stirred 18 hours.Mixture is filtered enter in the little glass bottle, and by HPLC purifying (5-90%, acetonitrile/water/0.1%TFA).Merge desired wash-out level part, and remove acetonitrile.Then, with EtOAc extraction organism.Make the organic substance drying of merging, filter, and vacuum-evaporation, so that 20 milligrams of desired products to be provided, for white solid (50%, M+H ⁺: 483).

Following embodiment is according to about the illustrated step of embodiment 24, uses corresponding amine and (indoles-1-yl) acetate of functional groupization suitably to synthesize.% productive rate and M+H ⁺Be presented at parenthetic.

N-methyl-2-(3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl } indoles-1-yl) ethanamide (46%, M+H ⁺: 497);

N-cyano methyl-2-(3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl } indoles-1-yl) ethanamide (49%, M+H ⁺: 522);

N-carbamyl ylmethyl-2-(3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl } indoles-1-yl) ethanamide (50%, M+H ⁺: 540);

1-morpholine-4-base-2-(3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl } indoles-1-yl) ethyl ketone (44%, M+H ⁺: 553);

N-carbamyl ylmethyl-N-methyl-2-{3-[2,2,2-three fluoro-1-hydroxyl-1-(1-p-tolyl-1H-indazole-5-yl) ethyl] indoles-1-yl } ethanamide (44%, M+H ⁺: 550);

N-carbamyl ylmethyl-2-{3-[2,2,2-three fluoro-1-hydroxyl-1-(1-p-tolyl-1H-indazole-5-yl) ethyl] indoles-1-yl } ethanamide (40%, M+H ⁺: 536);

N-(2-methoxy ethyl)-N-methyl-2-{3-[2,2,2-three fluoro-1-hydroxyl-1-(1-p-tolyl-1H-indazole-5-yl) ethyl] indoles-1-yl } ethanamide (50%, M+H ⁺: 551);

N-(2-methoxy ethyl)-2-{3-[2,2,2-three fluoro-1-hydroxyl-1-(1-p-tolyl-1H-indazole-5-yl) ethyl] indoles-1-yl } ethanamide (49%, M+H ⁺: 537);

N-cyano methyl-2-{3-[2,2,2-three fluoro-1-hydroxyl-1-(1-p-tolyl-1H-indazole-5-yl) ethyl] indoles-1-yl } ethanamide (37%, M+H ⁺: 518);

N-methyl-2-{3-[2,2,2-three fluoro-1-hydroxyl-1-(1-p-tolyl-1H-indazole-5-yl) ethyl] indoles-1-yl } ethanamide (39%, M+H ⁺: 493); And

2-{3-[2,2,2-three fluoro-1-hydroxyl-1-(1-p-tolyl-1H-indazole-5-yl) ethyl] indoles-1-yl } ethanamide (35%, M+H ⁺: 479).

Embodiment 25:2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1H-indol-3-yl) ethanol

At room temperature, to indoles (0.037 gram, 0.320 mmole) in 4 milliliters of t-butyl methyl ether in stirred solution, add the solution (3M, in ether, 0.200 milliliter, 0.600 mmole) of ethyl-magnesium-bromide.Formed Dark grey solution was at room temperature stirred 45 minutes, then, add cupric iodide (0.032 gram, 0.170 mmole).Reaction mixture was at room temperature stirred 45 minutes.At room temperature, the solution (0.100 gram, 0.324 mmole in 2.0 milliliter t-butyl methyl ether) of ketone in t-butyl methyl ether is added in the reaction mixture, and reactant was at room temperature stirred 2 hours.2.0 milliliters of ice cold waters are added in the reactant, and reactant was at room temperature stirred 10 minutes.Reaction mixture is added in 10 milliliters of methylene dichloride, and makes formed dark throw out through CELITE

The pad of flocculating aids filters.Methylene dichloride is washed with 5 mL of saline,, filter with dried over sodium sulfate, and vacuum evaporating solvent.Make crude material pass through quick purification by silica gel column chromatography (with 80% hexane/EtOAc wash-out).Obtain desired product, be faint yellow solid (37% productive rate, M+H ⁺: 426).

Following embodiment is according to about the illustrated step of embodiment 25, uses the corresponding ketone and the indoles of functional groupization suitably to synthesize.Its % productive rate and M+H ⁺Be presented at parenthetic.

2,2, and 2-three fluoro-1-(5-fluoro-1H-indol-3-yl)-1-(1-p-tolyl-1H-indazole-5-yl) ethanol (48%, M+H ⁺: 440);

2,2,2-three fluoro-1-(5-fluoro-1H-indol-3-yl)-1-[1-(2-fluorophenyl)-1H-indazole-5-yl] ethanol (47%, M+H ⁺: 444);

2,2,2-three fluoro-1-(5-fluoro-1H-indol-3-yl)-1-[1-(4-p-methoxy-phenyl)-1H-indazole-5-yl] ethanol (46%, M+H ⁺: 456);

2,2, and 2-three fluoro-1-(5-fluoro-1H-indol-3-yl)-1-(1-pyridine-2-base-1H-indazole-5-yl) ethanol (35%, M+H ⁺: 427);

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(5-methoxyl group-4-Methyl-1H-indole-3-yl) ethanol (14%, M+H ⁺: 470);

1-(4-chloro-1H-indol-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (7%, M+H ⁺: 460);

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(6-methoxyl group-1H-indol-3-yl) ethanol (20%, M+H ⁺: 456);

1-(2,5-dimethyl-1H-indol-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (20%, M+H ⁺: 454);

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(7-methoxyl group-1H-indol-3-yl) ethanol (34%, M+H ⁺: 456);

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1H-indol-3-yl) ethanol (36%, M+H ⁺: 426);

1-(6-bromo-1H-indol-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (12%; M+H ⁺: 505);

1-(7-bromo-1H-indol-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (48%; M+H ⁺: 505);

1-(5-bromo-1H-indol-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (39%, M+H ⁺: 505);

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(5-Methyl-1H-indole-3-yl) ethanol (32%, M+H ⁺: 440);

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(2-Methyl-1H-indole-3-yl) ethanol (34%, M+H ⁺: 440);

1-(6-chloro-1H-indol-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (21%, M+H ⁺: 460);

1-(5-chloro-1H-indol-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (17%, M+H ⁺: 460);

1-(4-bromo-1H-indol-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (4%, M+H ⁺: 505);

2,2,2-three fluoro-1-(5-fluoro-1H-indol-3-yl)-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (24%, M+H ⁺: 444);

2,2,2-three fluoro-1-(4-fluoro-1H-indol-3-yl)-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (17%, M+H ⁺: 444);

2,2,2-three fluoro-1-(6-fluoro-1H-indol-3-yl)-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (26%, M+H ⁺: 444);

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(5-methoxyl group-1H-indol-3-yl) ethanol (29%, M+H ⁺: 456);

2,2,2-three fluoro-1-(7-fluoro-1H-indol-3-yl)-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (7%, M+H ⁺: 444);

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(6-Methyl-1H-indole-3-yl) ethanol (33%, M+H ⁺: 440);

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(7-Methyl-1H-indole-3-yl) ethanol (45%, M+H ⁺: 440); And

3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-5-nitrile (11%, M+H ⁺: 451).

Embodiment 26:2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-methyl-6-pyridin-3-yl-1H-indol-3-yl) ethanol

At room temperature, to bromo indole (0.100 gram, 0.193 mmole) in the solution in 5 milliliters of DMF, in microwave tube, add 3-pyridine boric acid (0.049 gram, 0.40 mmole), aqueous sodium carbonate (2M, 0.064 gram, 0.60 mmole) four (triphenyl phosphine) palladium (0) (0.023 gram, 0.020 mmole) in.With formed reaction mixture with nitrogen degasification 10 minutes.In Smith people's synthesizer, reactant was heated 2.5 hours down in 120 ℃.Make reactant be cooled to room temperature, and add 3 milliliters of saturated ammonium chloride solutions, so that the stopping of reaction.Add 10 milliliters of ethyl acetate, and with organic layer with the salt water washing, with dried over sodium sulfate, and filter.Make solvent vacuum-evaporation, and make crude material pass through the rapid column chromatography purifying, to obtain desired product (60%; M+H ⁺: 517).

Following embodiment is according to about the illustrated step of embodiment 26, uses the corresponding boric acid and the bromo indole of functional groupization suitably to synthesize.Its % productive rate and M+H ⁺Be presented at parenthetic.

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-methyl-6-pyridin-4-yl-1H-indol-3-yl) ethanol (60%, M+H ⁺: 517);

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(6-furans-2-base-1-Methyl-1H-indole-3-yl) ethanol (22%, M+H ⁺: 506); And

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-methyl-6-pyrimidine-5-base-1H-indol-3-yl) ethanol (25%, M+H ⁺: 518).

Embodiment 27:2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-{6-[(2-methoxy ethyl) methylamino]-1-Methyl-1H-indole-3-yl } ethanol

At room temperature, to bromo indole (0.050 gram, 0.096 mmole) in dioxane in stirring de-gassed solution, add N-(2-methoxy ethyl) methylamine (0.023 gram, 0.26 mmole), acid chloride (II) two-tertiary butyl xenyl phosphine catalyst is (0.005 milligram, catalytic amount) and sodium tert-butoxide (0.019 gram, 0.200 mmole).With formed reaction soln in the heating 2 hours down of 90 ℃ and nitrogen atmosphere.Make reaction mixture be cooled to room temperature, and through CELITE

The pad of flocculating aids filters.Vacuum evaporating solvent.Make crude material pass through the rapid column chromatography purifying, to obtain desired product (57%; M+H ⁺: 527).

Following embodiment is according to about the illustrated step of embodiment 27, uses the corresponding amine and the bromo indole of functional groupization suitably to synthesize.Its % productive rate and M+H ⁺Be presented at parenthetic.

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-[6-(2-methoxy ethyl amino)-1-Methyl-1H-indole-3-yl] and ethanol (47%, M+H ⁺: 513);

The 1-{6-[(2-dimethyl aminoethyl) methylamino]-1-Methyl-1H-indole-3-yl }-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (19%, M+H ⁺: 540);

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-methyl-5-morpholine-4-base-1H-indol-3-yl) ethanol (55%, M+H ⁺: 525);

1-[6-(2-dimethyl aminoethyl amino)-1-Methyl-1H-indole-3-yl]-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (43%, M+H ⁺: 526);

1-[5-(2-dimethyl aminoethyl amino)-1-Methyl-1H-indole-3-yl]-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (33%, M+H ⁺: 526);

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-methyl-6-tetramethyleneimine-1-base-1H-indol-3-yl) ethanol (41%, M+H ⁺: 509); And

2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-methyl-5-tetramethyleneimine-1-base-1H-indol-3-yl) ethanol (34%, M+H ⁺: 509).

Embodiment 28:N-(1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-yl) amsacrine

Step (a): in 50 ml flasks, place 2,2 among 3 milliliters of DMF, 2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-1-(1-methyl-7-nitro-1H-indol-3-yl) ethanol (180 milligrams, 0.37 mmole).To the 10%Pd/C that wherein adds catalytic amount.With the gas emptying, and add hydrogen.Make its triplicate, and reactant was stirred 48 hours under hydrogen atmosphere and room temperature.Then, reactant is filtered down in argon gas, and with EtOAc extraction filtrate.Make the organic substance drying of merging, filter, and vacuum-evaporation.Then, residue is dissolved among the minimum DMF, and by HPLC purifying (5-95% acetonitrile/water/0.1%TFA).Merge desired absorption peak, and remove acetonitrile.Then, with the saturated sodium bicarbonate solution alkalization aqueous solution, and extract with EtOAc.Merge organic substance, drying, and vacuum-evaporation are to provide 96 milligrams of desired product 1-(7-amino-1-Methyl-1H-indole-3-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol, for white solid (57%, M+H ⁺: 455).

Step (b): in 7 milliliters little glass bottles, place the 1-(7-amino-1-Methyl-1H-indole-3-yl)-2,2 among 1 milliliter of THF, 2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol (35 milligrams, 0.08 mmole, 1 equivalent).To wherein adding triethylamine (20 microlitres, 0.16 mmole, 2 equivalents), then be methane sulfonyl chloride (12 microlitres, 0.16 mmole, 2 equivalents).It was at room temperature stirred 2 hours.Then, reactant filtered enter in the little glass bottle of HPLC, and by HPLC purifying (5-95% acetonitrile/water/0.1%TFA).Merge desired wash-out level part, and remove acetonitrile.With saturated sodium bicarbonate solution this aqueous solution that alkalizes, and extract with EtOAc.Make the organic substance drying of merging, filter, and vacuum-evaporation, so that 12 milligrams of desired products to be provided, for tawny foam thing (29%, M+H ⁺: 533).

Embodiment 29:N-(1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-yl) amsacrine

Step (a): in 50 ml flasks, place the 1-methyl-3-{2 among 2 milliliters of THF and the 20 milliliters of 1M NaOH, 2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-methyl-formiate (357 milligrams, 0.72 mmole).It is at room temperature stirred.After 2 hours, add 10 milliliters of THF of another part, and reactant was heated 18 hours down at 50 ℃.At this moment, add 3 particulate solid NaOH, and continue heating.In again after 2 hours, add other 3 particulate NaOH, and reactant was stirred 72 hours down in 50 ℃.Make the reactant cooling, and be transferred to separating funnel, to wherein making it be acidified to pH 7 with saturated aqueous ammonium chloride.It is extracted with EtOAc, and makes the organic substance drying of merging, filter, and vacuum-evaporation, so that 280 milligrams of desired products to be provided, for the tawny solid (81%, M+H ⁺: 484).

Step (b): in 7 milliliters little glass bottles, place the 1-methyl-3-{2 among 1 milliliter of DMF, 2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-formic acid (50 milligrams, 0.1 mmole, 1 equivalent).To wherein adding triethylamine (79 microlitres, 0.6 mole, 6 equivalents), then be PyBOP (80 milligrams, 0.15 mmole, 1.5 equivalents).After 5 minutes, add ammonium chloride (55 milligrams, 1 mmole, 10 equivalents), reaction is added a cover, and reactant was at room temperature stirred 18 hours.Mixture is filtered carry out in the little glass bottle, and by HPLC purifying (5-95% acetonitrile/water/0.1%TFA).Merge desired wash-out level part, and remove acetonitrile.Make to contain water section and alkalize, and extract with EtOAc with saturated sodium bicarbonate aqueous solution.Make the organic substance drying of merging, filter, and vacuum-evaporation, so that 36 milligrams of desired products to be provided, for white solid (72%, M+H ⁺: 483).

Following embodiment is according to about the illustrated step of embodiment 29 steps (b), uses the corresponding amine and the indole-2-formate of functional groupization suitably to synthesize.Its % productive rate and M+H ⁺Be presented at parenthetic.

1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-formic acid methyl nitrosourea (70%M+H ⁺: 497);

1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-formic acid (2-cyano ethyl) acid amides (63%, M+H ⁺: 536);

1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-formic acid (2-methoxy ethyl) acid amides (79%, M+H ⁺: 541);

1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-formic acid (2-methoxy ethyl) methyl nitrosourea (77%＜M+H ⁺: 555);

1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-formic acid formamyl methyl nitrosourea (74%, M+H ⁺: 540);

1-methyl-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-formic acid Cyanomethyl amides (80%, M+H ⁺: 522); And

1-allyl group-3-{2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-the 1-hydroxyethyl }-1H-indoles-7-benzoic acid amides (66%, M+H ⁺: 509).

Embodiment 30:2,2,2-three fluoro-1-phenyl-1-(1-phenyl-1H-indoles-5-yl) ethanol

Step (a): under 0 ℃, to 1-phenyl-1H-indoles-5-nitrile (2.51 gram, 11.47 mmoles) at 60 milliliters of CH ₂Cl ₂In solution in, add DIBAL-H (1M, in THF, 16 milliliters, 16 mmoles).Formed yellow suspension was stirred 2 hours, then, pour in 30 milliliters of cold 1N HCl solution.Make biphasic system be cooled to 0 ℃, then, alkalize to pH 8 by adding saturated sodium bicarbonate aqueous solution.With three parts of each 20 milliliters of CH ₂Cl ₂Aqueous layer extracted.The organic phase that makes merging is filtered, then vacuum concentration with dried over sodium sulfate.Make crude material pass through quick purification by silica gel column chromatography (with 100%-80% hexane/EtOAc wash-out).Obtain desired product 1-phenyl-1H-indoles-5-formaldehyde, be faint yellow solid (1.77 grams, 70% productive rate; M+H ⁺: 222).

Step (b): under 0 ℃, in the solution of 1-phenyl-1H-indoles-5-formaldehyde (1.2 grams, 5.4 mmoles) in 10 milliliters of THF, add TMSCF ₃Solution in THF (0.9 gram, 6.4 mmoles).Formed yellow solution was stirred 15 minutes down at 0 ℃, then, interpolation tetrabutylammonium (TBAF) (1M, in THF, 1.6 milliliters, 1.6 mmoles).Make reaction mixture be warmed to room temperature, then, restir 14 hours.Make THF vacuum-evaporation, and formed residue is dissolved among 20 milliliters of EtOAc,,, filter with dried over sodium sulfate with three parts of each 25 ml waters and the washing of 25 mL of saline, and vacuum evaporating solvent.Make crude material pass through quick purification by silica gel column chromatography (with 80% hexane/EtOAc wash-out).Obtain desired product 2,2,2-three fluoro-1-(1-phenyl-1H-indoles-5-yl) ethanol is faint yellow solid (1.4 grams, 87.0% productive rate; M+H ⁺: 292).

Step (c): with 2,2,2-three fluoro-1-(1-phenyl-1H-indoles-5-yl) ethanol (1.4 grams, 4.8 mmoles) is at 20 milliliters of CH with Dess-Martin periodinane (2.4 grams, 5.6 mmoles) ₂Cl ₂In suspension at room temperature stirred 12 hours.Reaction mixture is added in 150 milliliters of hexanes, and makes formed white depositions through CELITE

The pad of flocculating aids filters.The organic solution that merges is washed with three parts of each 25 milliliters of sodium bicarbonates and a 25 mL of saline,, filter with dried over sodium sulfate, and vacuum evaporating solvent.Make crude material pass through quick purification by silica gel column chromatography (with 85% hexane/EtOAc wash-out).Obtain desired product 2,2,2-three fluoro-1-(1-phenyl-1H-indoles-5-yl) ethyl ketone is white solid (1.3 grams, 91.0% productive rate; M+H ⁺: 290).

Step (d): at room temperature,, in the solution of 2-three fluoro-1-(1-phenyl-1H-indoles-5-yl) ethyl ketones (50.0 milligrams, 0.2 mmole) in 0.5 milliliter of THF, add phenyl-magnesium-bromide (1.0M, 1.0 milliliters, 1.0 mmoles) to 2,2.Solution was stirred 12.0 hours under this temperature.With 2 milliliters of saturated aqueous ammonium chlorides and 3.0 ml waters, make the stopping of reaction.With three parts of each 5 milliliters of EtOAc aqueous layer extracted, and the organic layer that makes merging filters with dried over sodium sulfate, and vacuum evaporating solvent.Make crude material pass through quick purification by silica gel column chromatography (with 100%-85% hexane/EtOAc wash-out).Obtain desired product 2,2,2-three fluoro-1-phenyl-1-(1-phenyl-1H-indoles-5-yl) ethanol, for white solid (49.0 milligrams, 80% productive rate; M+H ⁺: 368).

Following embodiment is according to about the illustrated step of embodiment 30 steps (d), uses the refined or equivalent organometallic reagent of corresponding Green synthetic.The yield percentage of reactant and M+H ⁺Be presented at parenthetic.

2,2, and 2-three fluoro-1-(4-fluoronaphthalene-1-yl)-1-(1-phenyl-1H-indoles-5-yl) ethanol (66%, M+H ⁺: 436); And

2,2, and 2-three fluoro-1-naphthalene-1-base-1-(1-phenyl-1H-indoles-5-yl) ethanol (78%, M+H ⁺: 418).

Embodiment 31:N-{3-[2,2,2-three fluoro-1-hydroxyl-1-(1-phenyl-1H-indoles-5-yl) ethyl] phenyl } ethanamide

Step (a): in 100 ml flasks, place 1-[3-(2, the 5-dimethyl pyrrole-1-yl) phenyl in 7 milliliters of EtOH and 3 ml waters]-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (112 milligrams, 0.24 mmole, 1 equivalent).To wherein adding hydroxylamine hydrochloride (168 milligrams, 2.4 mmoles, 10 equivalents), and reactant was refluxed 18 hours.Then, remove EtOH, and reactant is diluted with EtOAc.Then, it is alkalized with saturated sodium bicarbonate aqueous solution, be transferred to separating funnel, and extract with EtOAc.Make the organic substance drying of merging, filter, and vacuum-evaporation.Make residue pass through the rapid column chromatography purifying, so that 25 milligrams of 1-(3-aminophenyl)-2,2 to be provided, 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol, for light orange solid (70%, M+H ⁺: 462).

Step (b): in 10 ml flasks, place the 1-(3-aminophenyl)-2,2 in 1 milliliter of pyridine, 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (20 milligrams, 0.05 mmole, 1 equivalent).To wherein adding 1 Acetyl Chloride 98Min..After 2 hours, remove pyridine, and make residue pass through the flash chromatography purifying, so that 16.4 milligrams of desired products to be provided, for white solid (74%, M+H ⁺: 426).

Embodiment 32:1-(1-allyl group-1H-indol-3-yl)-1-[1-(4-fluorophenyl)-1H-indazole-5-yl]-2-methyl-prop-1-alcohol

Step (a): in 250 ml flasks, place 5-bromo-1-(4-the fluorophenyl)-1H-indazole (3.5 grams, 11.5 mmoles, 1.1 equivalents) among 50 milliliters of anhydrous THF.Make it be cooled to-78 ℃.In another little glass bottle, place the 1-allyl group-1H-indole-3-formaldehyde (2.0 grams, 10.8 mmoles, 1 equivalent) among 5 milliliters of THF, and make it be cooled to-78 ℃.N-BuLi (2.5M, in hexane, 4.7 milliliters, 11.5 mmoles, 1.1 equivalents) promptly is added in 5-bromo-1-(4-fluorophenyl)-1H-indazole by syringe, at this moment, adds the solution of 1-allyl group-1H-indole-3-formaldehyde with portion.Reactant was stirred 30 minutes down in-78 ℃, at this moment, make the stopping of reaction, and make it return back to room temperature with water.Then, reactant is diluted with salt solution, and extract with EtOAc.Make the organic substance drying of merging, filter, and vacuum-evaporation.Make residue pass through flash chromatography purifying (0-30%EtOAc/ hexane), so that 1.5 gram (1-allyl group-1H-indol-3-yl)-[1-(4-fluorophenyl)-1H-indoles-5-yl] methyl alcohol to be provided, for the tawny solid (35%, M+H ⁺: 398).

Step (b): in 100 ml flasks, place 50 milliliters of CH ₂Cl ₂In (1-allyl group-1H-indol-3-yl)-[1-(4-fluorophenyl)-1H-indoles-5-yl] methyl alcohol (1.3 gram, 3.2 mmoles, 1 equivalent).Make it be cooled to 0 ℃, to wherein adding pyridinium chlorochromate

(PCC; 764 milligrams, 3.5 mmoles, 1.1 equivalents).After 5 minutes, remove ice bath, and reactant was at room temperature stirred 18 hours.With reactant transfer to separating funnel, and with CH ₂Cl ₂Dilute, and wash with saturated sodium bicarbonate aqueous solution.Remove organism, make its drying, filter, and vacuum-evaporation.Make residue pass through flash chromatography purifying (0-30%EtOAc/ hexane), so that 820 milligrams (1-allyl groups-1H-indol-3-yl)-[1-(4-fluorophenyl)-1H-indazole-5-yl] to be provided ketone, be the tawny solid, use and need not to be further purified (65%, M+H ⁺: 396).

Step (c): in 25 ml flasks, place (1-allyl group-1H-indol-3-yl)-[1-(4-the fluorophenyl)-1H-indazole-5-yl] ketone (100 milligrams, 0.3 mmole, 1 equivalent) among 5 milliliters of THF.Make it be cooled to-78 ℃.To wherein dripping sec.-propyl lithium (0.7M, in pentane, 0.43 milliliter, 1.2 equivalents).Then, reactant was stirred 30 minutes.Then, with water diluting reaction thing, and make it return back to room temperature.Mixture is transferred to separating funnel, and extracts with EtOAc.Make the organic substance drying of merging, filter, and vacuum-evaporation.Make residue pass through flash chromatography purifying (0-20%EtOAc/ hexane), so that 21 milligrams of desired compounds to be provided, for white solid (19%, M+H ⁺: 440).

Following embodiment is according to synthetic about the illustrated step of embodiment 32 steps (c), makes refined or equivalent organometallic reagent of corresponding Green and desired dibenzyl reactive ketone.The yield percentage of reactant and M+H ⁺Be presented at parenthetic.

1-(1-phenyl-1H-indazole-5-yl)-1-quinolyl-4 ethanol (65%, M+H ⁺: 366);

1-(1-phenyl-1H-indazole-5-yl)-1-quinolyl-4 third-1-alcohol (30%, M+H ⁺: 380);

1-(4-fluoronaphthalene-1-yl)-1-(1-phenyl-1H-indazole-5-yl) third-1-alcohol (81%, M+H ⁺: 397); And

1-(1-allyl group-1H-indol-3-yl)-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] and third-1-alcohol (18%, M+H ⁺: 426).

Embodiment 33:2,2,2-three fluoro-1-(4-fluoro-3-hydroxymethyl phenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol

Step (a): at room temperature, to 2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethyl ketone (0.150 gram, 0.517 mmole) in the solution in THF, add 3-(1, the 3-dioxane oneself-the 2-yl) 4-fluorophenyl magnesium bromide (0.25M, in THF, 6.0 milliliters, 1.5 mmoles).Formed solution was at room temperature stirred liquid.With saturated ammonium chloride solution, make the stopping of reaction.Add ethyl acetate, and,, and filter with dried over sodium sulfate with salt water washing organic layer.Make solvent vacuum-evaporation, and make crude material pass through the rapid column chromatography purifying, with obtain desired product 1-(3-1, the 3-dioxane oneself-2-base-4-fluorophenyl)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (82%, M+H ⁺: 473).

Step (b): at room temperature, to 1-(3-1, the 3-dioxane oneself-2-base-4-fluorophenyl)-2,2, in the solution of 2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol (0.2 gram, 0.423 mmole) in THF, add HCl solution (2M, 5 milliliters).Formed solution at room temperature stirred spend the night.By saturated aqueous sodium carbonate, make reaction mixture be neutralized to pH 7.Add ethyl acetate, and,, and filter with dried over sodium sulfate with salt water washing organic layer.Make solvent vacuum-evaporation, and make crude material pass through the rapid column chromatography purifying, obtaining desired product 2-fluoro-5-[2,2,2-three fluoro-1-hydroxyl-1-(1-phenyl-1H-indazole-5-yl) ethyl] phenyl aldehyde (48%, M+H ⁺: 415).

Step (c): at room temperature, to 2-fluoro-5-[2,2,2-three fluoro-1-hydroxyl-1-(1-phenyl-1H-indazole-5-yl) ethyl] phenyl aldehyde (0.04 gram, 0.097 mmole) in methylene dichloride in stirred solution, add sodium triacetoxy borohydride (0.032 gram, 0.15 mmole).Reaction-ure mixture at room temperature stirred spend the night, then, with 3 milliliters of methylene dichloride and 4 milliliters of saturated sodium bicarbonate aqueous solutions dilutions.Add 10 milliliters of ethyl acetate of an ancient woman's ornament, and,, and filter with dried over sodium sulfate with salt water washing organic layer.Make solvent vacuum-evaporation, and make crude material pass through the rapid column chromatography purifying, obtaining desired product 2,2,2-three fluoro-1-(4-fluoro-3-hydroxymethyl phenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol (80%, M+H ⁺: 417).

Embodiment 34:3-[2,2,2-three fluoro-1-hydroxyl-1-(1-phenyl-1H-indazole-5-yl) ethyl] phenol

Under 0 ℃, to 2,2,2-three fluoro-1-(3-methoxyphenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol (0.054 gram, 0.136 mmole) is at CH ₂Cl ₂In solution in, drip BBr ₃(1M is at CH ₂Cl ₂In, 1.36 milliliters, 1.36 mmoles).Formed solution was stirred 2 days down in 5 ℃.Make reactant be warmed to room temperature, then,, make the stopping of reaction with 2 ml methanol.Ethyl acetate is added in the reactant, and,, and filters with dried over sodium sulfate with salt water washing organic layer.Make solvent vacuum-evaporation, and make crude material pass through the rapid column chromatography purifying, obtaining desired compound 3-[2,2,2-three fluoro-1-hydroxyl-1-(1-phenyl-1H-indazole-5-yl) ethyl] phenol (38%, M+H ⁺: 389).

The assessment of biological property

Competitive in conjunction with detecting by fluorescence polarization, the assessment The compounds of this invention combines with steroid receptor.Among the U. S. application publication number US 2003/0017503 that the detailed description of reorganization glucocorticoid acceptor (GR) mixture that is used to detect about preparation, record are to submit on May 20th, 2002, be incorporated herein by reference in full with it at this.The preparation of the dexamethasone probe of tetramethyl-rhodamine (TAMRA)-mark, will with the normative document method (people such as M.Pons, J.Steroid Biochem., 1985, 22, the 267-273 page or leaf).

A. The glucocorticoid receptor competition is in conjunction with detection

The sign of step 1. fluorescent probe

At first measure the maximum excitation and the emission wavelength of fluorescent probe.The example of these probes is the dexamethasone of rhodamine (TAMRA)-mark.

Then, in titration experiments, measure the avidity of probe to steroid receptor.The fluorescence polarization value of probe in detecting damping fluid is on the SLM-8100 photofluorometer, measures with above-mentioned exciting with emission maximum.The liquid part that adds the expression vector lysate, and after each the adding, measure the fluorescence polarization effect, till not finding that polarization value further changes.From be bonded to the polarization value that probe obtains for lysate, calculate the dissociation constant of probe with the nonlinear least square regression analysis.

The screening of step 2. probe binding inhibitors

This detection is to use fluorescence polarization (FP), so that the competition of the dexamethasone of testing compound and tetramethyl-rhodamine (TAMRA)-mark is carried out quantitatively the binding ability from human glucocorticoid acceptor (GR) mixture of insect expression system.The detection damping fluid is: 10mM TES, 50mM KCl, 20mMNa ₂MoO ₄2H ₂O, 1.5mM EDTA, 0.04%w/v CHAPS, 10%v/v glycerine, the 1mM dithiothreitol (DTT), pH 7.4.Testing compound is dissolved to 1mM in pure DMSO, in the detection damping fluid that replenishes 10%v/v DMSO, further is diluted to the 10x detectable level then.Testing compound in containing the buffer reagent of 10%DMSO, on the polypropylene board of 96-hole, is diluted with continuity ground under the 10x detectable level.The association reaction mixture is in the black Dynex titer plate of 96-hole, make to each hole by adding following detection composition in succession: 15 microlitre 10x testing compound solutions, 85 microlitres with the baculovirus lysate that contains GR of dilution in 1: 170, reach the dexamethasone of 50 microlitre 15nMTAMRA-marks in detecting damping fluid.Positive controls is not for containing the reaction mixture of testing compound; Negative control group (blank test) is for containing the reaction mixture of 0.7 μ M to 2 μ M dexamethasone.The association reaction thing was at room temperature cultivated 1 hour, then be set to 550 nanometers excite with 580 nanometers emissions under, and install in the LJL analyzer of rhodamine 561 dichroic mirrors, read fluorescence polarization.IC ₅₀Value is that the iteration nonlinear curve by the FP signal data fits to 4-parameter l ogistic equation and records.

Can assess discovery in conjunction with the combination of the compound of glucocorticoid acceptor, with the selectivity of assessment compound to GR to progesterone receptor (PR), estrogen receptor (ER) and mineralocorticoid (MR).The experimental procedure of PR and MR, identical with above-mentioned GR method, but following condition exception: PR insect cell lysate is with dilution in 1: 7.1, and the MR lysate is with dilution in 1: 9.4.The PR probe is the mifepristone (mifepristone) of TAMRA-mark, be used in the detection with the final concn of 5nM, and negative control group (blank test) is for containing the reaction of the mifepristone under 0.7 μ M to the 2 μ M.

The similar above-mentioned plan case of ER experimental procedure, but use PanVera test kit acceptor, fluorescein-labeled probe.Detect composition and be with as above-mentioned equal volume make, be 15nM to produce ER, and be the last detectable level of 1nM the ES2 probe.In addition, the composition of adding is the correction of above-mentioned detection in proper order: at first probe is added to plate, then is acceptor and testing compound.Plate is being installed fluorescein 505 dichroic mirrors, setting 485 nanometers and excite in the LJL analyzer with the emission of 530 nanometers and read.

Discovery is in conjunction with the compound of glucocorticoid acceptor, can be by detection (C.M.Banberger and the H.M.Schulte that quotes from the background of invention, Eur.J.Clin.Invest., 2000,30 (replenish 3) 6-9) or the detection by hereinafter described, assessment transactivation and trans-repression dissociates.

B. The glucocorticoid recipient cell detects

1. aromatase enzyme inducing in inoblast (cell detection of transactivation)

Dexamethasone, the part of a kind of synthetic glucocorticoid acceptor (GR) can bring out the expression of aromatase enzyme in human foreskin inoblast.Testosterone is measured the activity of aromatase enzyme to the conversion of estradiol in substratum.Assessment shows the compound be bonded to GR brings out aromatase activity in human foreskin inoblast ability.

With human foreskin inoblast (ATCC catalog number CRL-2429, name is called CCD112SK) at preceding 5 days that use, on 96 orifice plates, with every hole 50, be seeded under 000 cell in the IscoveShi modification Dulbecco substratum (GibcoBRL life Technologies catalog number 12440-053), through replenishing filtering FBS of 10% charcoal (Clonetech catalog number SH30068) and gentamicin (GibcoBRLlife Technologies catalog number 15710-064).Testing the same day, the substratum in the hole is replaced with new substratum.Is 10 with cell with final concn ^-5M to 10 ^-8The testing compound of M and final concn are that 300 nanograms/milliliter testosterones are handled.Each hole cumulative volume is 100 microlitres.Sample is made double.Control wells comprises: (a) only accept the hole of testosterone, and (b) accept the hole that testosterone and 2 μ M dexamethasone bring out with the maximum that aromatase enzyme is provided.With plate in 37 ℃ of following overnight incubation (15 to 18 hours), and when cultivate finishing the enrichment supernatant liquid.Utilize the ELISA test kit (, deriving from U.S. laboratory product catalog number 020-DR-2693) of estradiol to measure the estradiol in the supernatant liquor, carry out according to shop instruction by the ALPCO preparation.ELISA signal in the amount of estradiol and each hole is inversely proportional to.The degree of the aromatase enzyme that testing compound brings out is represented with the per-cent with respect to dexamethasone.Fit the EC that derives testing compound by nonlinear curve ₅₀Value.

2. the inhibition (cell detection of trans-repression) that IL-6 produces in the inoblast

Pro-inflammatory cytokine IL-1 stimulating human foreskin inoblast produces IL-6.This kind Inflammatory response when measuring by the generation of IL-6, can be suppressed by dexamethasone effectively, and the latter is the part of a kind of synthetic glucocorticoid acceptor (GR).In human foreskin inoblast, assessment suppresses the ability that IL-6 produces to GR bonded compound.

One day before use, with human foreskin inoblast (ARCC catalog number CRL-2429) on 96 orifice plates, with every hole 5, be seeded under 000 cell in the IscoveShi modification Dulbecco substratum (GibcoBRL life Technologies catalog number 12440-053), through replenishing filtering FBS of 10% charcoal (Clonetech catalog number SH30068) and gentamicin (GibcoBRL life Technologies catalog number 1710-064).Inferior day, the substratum in the hole is replaced with new substratum.With cell is IL-1 (rhIL-1 α, the R﹠amp of 1 nanograms/milliliter with final concn; D System, catalog number 200-LA) and final concn be 10 ^-5M to 10 ^-8The testing compound of M is handled, and cumulative volume is 200 microlitres.Sample is made double.The background control wells is not accepted testing compound or IL-1.IL-1 is only accepted in the positive control hole, and represents the IL-6 of maximum (or 100%) amount to produce.With plate in 37 ℃ of following overnight incubation (15 to 18 hours), and when cultivate finishing the enrichment supernatant liquid.By the ELISA test kit (MedSystems Diagnostics GmbH, Vienna, Austria, catalog number BMS213TEN) of IL-6 being measured the IL-6 content in the supernatant liquid, measure according to shop instruction.The degree that IL-6 is suppressed by testing compound is represented with the per-cent with respect to positive controls.The IC of testing compound ₅₀Value is to fit derivation by nonlinear curve.

Compound can be measured by any detection in conjunction with the assessment of the agonist or the antagonistic activity of glucocorticoid acceptor.

3. tyrosine aminotransferase in the rat hepatoma cell (TAT) inductive is regulated

Test compounds is induced the agonist or the antagonistic activity of tyrosine aminotransferase (TAT) in rat hepatoma cell.

With the H4-II-E-C3 cell in 96 orifice plates (20,000 cell/100 microlitres/holes), overnight incubation in containing 10% heat inactivation FBS and 1% nonessential amino acid whose MEM substratum.Every other day, dexamethasone or the testing compound (be dissolved in DMSO, last DMSO concentration be 0.2%) of cell with indicated concentration stimulated 18 hours.Control cells is handled with 0.2%DMSO.After 18 hours, cell is carried out cracking in containing the damping fluid of 0.1%TritonX-100, and in photometer detects, will be with tyrosine and α-Tong Wuersuan as substrate, measurement TAT activity.

In order to measure antagonistic activity, before being applied to cell, testing compound soon, adds dexamethasone (concentration range 3 * 10 ^-9M to 3 * 10 ^-8M) stimulate liver cancer cell in advance.With the non-selective GR/PR antagonist of steroid mifepristone in contrast.

4. the MMTV-Luc inductive is regulated in the HeLa cell

Test compounds is at the agonist or the antagonistic activity of inducing MMTV-(mouse mammary tumour virus) promotor in the HeLa cell.

With HeLa cytotostatic ground and pHHLuc-plasmid co-transfection, this plasmid contains and is cloned at luciferase gene (Norden, 1988) the MMTV-LTR fragment of upstream (200 to+100) with respect to transcripting start point, and constitute upward selectivity microbiotic GENETICIN

Express drug-fast pcDNA3.1 plasmid (Invitrogen).Screening has the best inductive clone of MMTV-promotor, and is used in further experiment.

Cell is replenished overnight incubation in the DMEM substratum of 3% (through the calf serum that charcoal is handled) not using phenolsulfonphthalein, be transferred to 96 orifice plates (15,000 cells/100 microlitres/hole) then.Every other day, sting activating signal activation MMTV-promotor by adding the testing compound or the dexamethasone (final concn 0.2%) that have been dissolved among the DMSO.Control cells is only handled with DMSO.After 18 hours, cell with lysis agent (Promega, catalog number E1531) cracking, is added luciferase detection reagent (Promega, catalog number E1501), and (BMG, Offenburg) measurement is luminous to use luminometer.

In order to measure antagonistic activity, before being applied to cell, testing compound soon, adds dexamethasone (3 * 10 ^-9M to 3 * 10 ^-8M) stimulate the MMTV-promotor in advance.Will be in contrast with the non-selective GR/PR antagonist of steroid mifepristone.

5. the adjusting that IL-8 in the U937 cell is produced

In the U-937 cell, test compounds is to the inductive IL-8 of inhibition LPS-institute excretory agonist or antagonistic activity that GR mediated.

The U-937 cell was cultivated 2 to 4 days in the RPMI1640 substratum that contains 10%CCS (through the calf serum that charcoal is handled).With cell transfer to 96 orifice plate (40,000 cells/100 microlitres/hole), and under dexamethasone or testing compound (being dissolved among the DMSO final concn 0.2%) existence or not existing, stimulate with 1 mcg/ml LPS (being dissolved among the PBS).Control cells is handled with 0.2%DMSO.After 18 hours, be to utilize " the human IL-8 combination of OptEIA " (Pharmingen, catalog number 2654KI) by the IL-8 concentration in the ELISA measurement cell supernatant liquid.

In order to measure antagonistic activity, before being applied to cell, testing compound soon, adds dexamethasone (3 * 10 ^-9M to 3 * 10 ^-8M) suppress the IL-8 secretion that LPS-regulated.Will be in contrast with the non-selective GR/PR antagonist of steroid mifepristone.

6. the adjusting that ICAM-Luc expresses in the HeLa cell

Test compounds suppresses the agonist or the antagonistic activity of the activation of the TNF-inductive ICAM-of α-institute promotor in the HeLa cell.

Make HeLa cytotostatic ground and plasmid co-transfection, this plasmid contain the human ICAM-promotor that is cloned in the luciferase gene upstream the 1.3kb fragment (1353 to-9, with respect to transcripting start point, Ledebur and Parks, 1995), and constitute to go up to microbiotic GENETICIN

Show drug-fast pcDNA3.1 plasmid (Invitrogen).Screening has the best inductive clone of ICAM-promotor, and is used in the further experiment.With cell transfer to 96 orifice plates (15,000 cell/100 microlitres/holes) that contain the DMEM substratum that replenishes 3%CCS.Every other day, by adding 10 nanograms/milliliter reorganization TNF-α (R﹠amp; D system, catalog number 210-TA), induce the activation of ICAM-promotor.Simultaneously, cell is handled with testing compound or dexamethasone (being dissolved among the DMSO final concn 0.2%).Control cells is only handled with DMSO.After 18 hours, (Promega, catalog number E1531) makes lysis with cell cracking agent, adds luciferase detection reagent (Promega, catalog number E1501), and (BMG, Offenburg) measurement is luminous to use luminometer.

In order to measure antagonistic activity, before testing compound is applied to cell soon, by adding dexamethasone (3 * 10 ^-9M to 3 * 10 ^-8M), the TNF-α-institute inductive activation that suppresses the ICAM-promotor.Will be in contrast with the non-selective GR/PR antagonist of steroid mifepristone.

Generally speaking, the preferred field of activity in above-mentioned detection, between 0.1nM and 10 μ M, preferred field of activity is 0.1nM to 1 μ M, and most preferred field of activity is 0.1nM to 100nM.

Representative compounds of the present invention is tested, and shows the activity as the conditioning agent of glucocorticoid receptor function in one or more above-mentioned detection.For example, following representative compounds of the present invention at GR in conjunction with confirming effective active (between 0.1nM and 100nM) in detecting:

1-biphenyl-3-base-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(3-chloro-phenyl-)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-naphthalene-1-base-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(3-fluorophenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(4-fluorophenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(4-chloro-phenyl-)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl)-1-quinolyl-4 ethanol;

2,2,2-three fluoro-1-(1H-indoles-4-yl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1,1,1-three fluoro-3-phenyl-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl)-1-quinolyl-4 ethanol;

1-1,3-benzodioxole-4-base-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol; And

1-(2,2-two fluoro-1,3-benzodioxole-4-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol.

Following The compounds of this invention produces by suppressing IL-6 in inoblast (about the cell tests of trans-repression), confirms agonist activity:

2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl)-1-quinolyl-4 ethanol;

2,2,2-three fluoro-1-naphthalene-1-base-1-(1-phenyl-1H-indazole-5-yl) ethanol; And

1-(3-chloro-4-fluorophenyl)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol.

The treatment using method

As above-mentioned pointed, The compounds of this invention can be used for regulating the glucocorticoid function of receptors.When so carrying out, these compounds mediate on the morbid state and symptom of the adjusting that maybe will do well out of the glucocorticoid function of receptors by the glucocorticoid function of receptors in treatment, have therepic use.

When The compounds of this invention is regulated the glucocorticoid function of receptors, it has extremely useful anti-inflammatory and antiallergic property, immunosuppression and anti-proliferative activity, and it can be used as medicine and is used for the patient, particularly with pharmaceutical compositions as mentioned below, is used for the treatment of morbid state and symptom.

Agonist compound according to the present invention can be used as medicine and is used for the patient, in order to treat following morbid state or the indication that is accompanied by inflammatory, supersensitivity and/or hyperplasia process:

(i) lung disease: any origin chronic, block pulmonary disorder, particularly bronchial asthma and chronic obstruction tuberculosis (COPD); Adult respiratory distress syndrome (ARDS); Bronchiectasis; The bronchitis of various origins; The restrictive lung disease of form of ownership, particularly supersensitivity alveole inflammation; The pulmonary edema of form of ownership, particularly toxic pulmonary edema; The tissue space lung disease of the form of ownership of any origin, for example diversity pneumonia; And sarcoidosis and granulomatosis, particularly BoeckShi disease.

(ii) rheumatism or autoimmune disease or joint disease: the rheumatism of form of ownership, especially rheumatic arthritis, acute rheumatic fever and polymyalgia rheumatism; Reactive arthritis; Rheumatic parenchyma disease; The inflammatory parenchyma disease of other origins; Sacroiliitis symptom on sex change joint disease (joint disease); Traumatic arthritis; The collagen disease of any origin, for example systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, Sjogren syndrome, StillShi disease and Felry syndrome;

(iii) anaphylactic disease: the anaphylaxis of form of ownership, for example vasoneurosis oedema, hay fever, insect bite, to the anaphylaxis of medicine, blood derivatives, contrast medium etc., anaphylactic shock (anaphylaxis), urticaria, vasoneurosis oedema and contact dermatitis;

(iv) vasculitis disease: joint knot property panarteritis, joint knot property polyarteritis, temporalis arteritis, Wegner granulomatosis, giant cells sacroiliitis and erythema nodosum;

(v) tetter: atopic dermatitis, particularly in children; Psoriasis; The red fervent rash of hair; Because of the erythema disease that various cause of disease triggered, for example ray, chemical, burn etc.; The bleb tetter; The syndromic disease of lichen sample; The disease of scratching where it itches (for example supersensitivity origin person); Sebum leaks dermatitis; Rosacea; Pemphigus vulgaris; Dermatostomatitis; Balanitis; Cysthitis; Hair drops, as occurs in person in family's shape baldness; And cutaneous T cell lymphoma;

(vi) ephrosis: nephrotic syndrome; And all types of ephritis, for example glomerulonephritis;

(vii) hepatopathy: acute liver cell is decomposed; The acute hepatitis of various origins, for example virus, poisonous substance, medicine cause; And chronic attack and/or Chronic Intermittent hepatitis;

(viii) gastrointestinal illness: inflammatory bowel disease, for example regional enteritis (clone disease), ulcerative colitis; Gastritis; Reflux esophagitis (reflux oesophagitis); And the gastro-enteritis of other origins, for example non-aphthae tropicae;

(ix) proctology disease: anal eczema; The crack; Hemorrhoid; And spontaneous rectitis;

(x) disease of eye: anaphylactic keratitis, uveitis or iritis; The binding film inflammation; Blepharitis; The optic nerve neuritis; Choroiditis; And common sense ophthalmia;

(xi) disease in ear, nose and throat (ENT) zone: allergic rhinitis or hay fever; External otitis for example causes because of institutes such as contact eczema, infection; And otitis media;

(xii) sacred disease: the cerebral edema that cerebral edema, particularly tumour are relevant; Multiple sclerosis; Acute encephalomyelitis; Meningitis; Acute spinal cord injury; Apoplexy; And various forms of outbreaks, for example nodding spasm;

(xiii) hematologic disease: acquired hemolytic anemia; And spontaneous thrombocytopenia;

(xiv) tumor disease: acute lymphoblastic leukemia; Malignant lymphoma; Lymphogranulomatosis; Lymphosarcoma; Epitaxy shifts, particularly in breast, segmental bronchus and tumor of prostate;

(xv) endocrinopathy: endocrine ophthalmocace; The internal secretion orbital disease; Tiroidina poison crisis; The deQuervainShi thyroiditis; Struma lymphomatosa; The BasedowShi disease; The granuloma thyroiditis; Struma lymphomatosa; And GraveShi disease;

(xvi) organ and tissue transplantation, and graft-right-host disease;

(xvii) Xiu Ke serious state, for example septic shock, anaphylactic shock and system's Inflammatory response syndrome (SIRS);

(xviii) alternative medicine: congenital primary adrenal insufficiency, for example suprarenal gland sexual reproduction device syndrome; The day after tomorrow primary adrenal insufficiency, for example AddisonShi disease, autoimmunization paranephritis, infect back, tumour, transfer etc.; Congenital supervention adrenal insufficiency, for example congenital pituitary body hypofunction; Reach the supervention adrenal insufficiency day after tomorrow, for example infect back, tumour, transfer etc.;

(xix) pain of inflammatory origin, for example pain in the back; And

(xx) various other diseases states or symptom comprise type i diabetes (insulin-dependent diabetes), osteoarthritis, Guillain-Barre syndrome, restenosis behind the percutaneous transluminal coronary angioplasty, the alzheimer's disease, acute and chronic pain, atherosclerosis, perfusion injury again, bone-resorbing disease, congestive heart failure exhausts, myocardial infarction, thermal damage, the multiple organ injury of wound supervention, acute purulent meningitis, necrotizing enterocolitis, and and hemodialysis, related syndrome that white cell separates and granulocyte is transfused blood.

In addition, compound according to the present invention not can be used for treating in the synthetic glucocorticoid treatment of the above-mentioned use of mentioning, just with its treatment or will with any other morbid state of its treatment or symptom (consult, H.J.Hatz for example, Gluocorticoide:Immunologische Grundlagen, Pharmakologie Und Therapierichtlinien[glucocorticoid: amynologic basis, pharmacology and treatment are guided], Stuttgart:Verlagsgesellschaft mbH, 1998, be incorporated herein by reference in full with it at this).Above-mentioned mentioned most of or all indications (i) are described in detail in H.J.Hatz to (xx), Gluocorticoide: Immunologische Grundlagen, Pharmakologie und TherapierichtlinienIn.In addition, The compounds of this invention also can be above-mentioned that list or (comprise in the prior art) illness beyond the mentioned or debater of institute herein in order to treat.

According to agonist compounds of the present invention, no matter be complete antagonist or partial antagonist, can be used as medicine and be used for the patient, be used for the treatment of following morbid state or indication (but being not limited to): type ii diabetes (non-insulin-dependent diabetes mellitus (NIDDM)); Fat; Cardiovascular disorder; Hypertension; Arteriosclerosis; Sacred disease is as psychosis and depression; Suprarenal gland and pituitary tumor; Glaucoma; And based on the ACTH secreting tumor Cushing syndrome of pituitary adenoma for example.Particularly, The compounds of this invention can be used for treating the related morbid state of lipid acid metabolism and the indication of obesity and all and imbalance, as hypertension, atherosclerosis and other cardiovascular disordeies.Will be with the The compounds of this invention that is the GR antagonist, it should be able to antagonism carbohydrate metabolism and lipid acid metabolism.Therefore, agonist compounds of the present invention can be used for treating all morbid states and the symptom of the carbohydrate, protein and the lipid metabolism effect that relate to increase, and comprises and can cause the katabolism for example morbid state and the symptom of muscle weakness (as the embodiment of protein metabolism effect).

The method that diagnosis utilizes

The compounds of this invention also can be used for diagnostic use, for commercial and other purposes as the competitive standard substance that combines in the detection.In these purposes, The compounds of this invention can compound itself form use, or it can be by connecting radioactivity same sex element, luminous, fluorescent marker or its analogue are modified, to obtain radioactivity same sex element, luminous or fluorescent probe, those skilled in the art are known as this area, and it is to be summarized in Handbook of Fluorescent Probes and ResearchChemicals, 6th Edition, R.P.Haugland (ed.), Eugene:Molecular Probes, 1996; Fluorescence and Luminescence Probes for Biological Activity, W.T.Mason (ed.), San Diego:Academic Press, 1993; Receptor-Ligand Interaction, APractical Approach, E.C.Hulme (ed.), Oxford:IRL Press, 1992, each is incorporated herein by reference in full with it.

General administration and pharmaceutical composition

When as drug use, The compounds of this invention is typically with the form administration of pharmaceutical composition.These compositions can use on the medicine skill known step to make, and comprise at least a The compounds of this invention.The compounds of this invention can be separately or with the adjuvant combination medicine-feeding, this adjuvant is strengthened the stability of The compounds of this invention, helps to contain these compound ground pharmaceutical composition administrations in certain embodiments, and the dissolving or the dispersion of increase are provided, the inhibition activity that increases provides adjunctive therapy etc.Can use alone according to compound of the present invention, or arrange in pairs or groups other according to active substance of the present invention, the material of optional other tool pharmacological activities of also arranging in pairs or groups.Generally speaking, The compounds of this invention is to treat or pharmaceutically significant quantity administration, to measure administration but can hang down, so that diagnosis or other purposes to be provided.

Particularly, The compounds of this invention can merge use with glucocorticoid or reflunomide.As above-mentioned pointed,, comprise the administration of reflunomide for the standard treatment of panimmunity and inflammatory conditions, it has ability (A.P.Truhan et al., Annals of Allergy, 1989 that suppress immunology and Inflammatory response, 62, pp.375-391; J.D.Baxter, Hospital Practice, 1992,27, pp.111-134; R.P.Kimberly, Curr.Opin.Rheumatol., 1992,4, pp.325-331; M.H.Weisman, Curr.Opin.Rheumatol., 1995,7, pp.183-190; W.Sterry, Arch.Dermatol.Res., 1992,284 (Suppl.), pp.S27-S29).Though be favourable in the treatment,, the use of reflunomide is accompanied by many side effects, and its scope is from slight extremely possibility life-threatening, when especially being accompanied by long-term and/or high dosage steroid consumption.Therefore, the method and the composition that get the reflunomide (being called as " steroid restraining effect ") that can use low effective dose are high expectations, to avoid undesired side effect.The compounds of this invention is by reaching desired result of treatment, and allows simultaneously to use than low dosage and administration number of times glucocorticoid or reflunomide still less, and these steroid restraining effects are provided.

The compounds of this invention with pure form or with the administration of suitable pharmaceutical composition, can make any mode of administration of accepting of pharmaceutical composition carry out.Therefore, that administration can be is for example oral, cheek mode (for example hypogloeeis mode), intranasal mode, parenteral mode, local mode, through skin mode, vagina mode or rectal, with solid, semisolid, lyophilized powder or liquid dosages form, for example tablet, suppository, pill, resilient flexible and hard gelatin capsule, powder, solution, suspension or aerosol or its analogue preferably are the unit dosage form that is fit to simple and easy administration of precise dosages.Described pharmaceutical composition comprises conventional medicine carrier or vehicle usually, reaches The compounds of this invention as promoting agent, and can comprise other drug agent, medicament, carrier, adjuvant, thinner, mediator or its combination in addition.These pharmaceutically acceptable vehicle, carrier or additive, and the method for preparing the pharmaceutical composition of using for various mode of administration, those skilled in the art are known for this area.The current state in present technique field is by for example Remington:The Science and Practice of Pharmacy, 20th Edition, A.Gennaro (ed.), Lippincott Williams ﹠amp; Wilkins, 2000; Handbook ofPharmaceutical Additives, Michael ﹠amp; Irene Ash (eds.), Gower, 1995; Handbookof Pharmaceutical Excipients, A.H.Kibbe (ed.), American Pharmaceutical Ass ' n, 2000; H.C.Ansel and N.G.Popovish, Pharmaceutical Dosage Forms and DrugDelivery Systems, 5th ed., Lea and Febiger, 1990 confirm; Each document all is incorporated herein by reference in full with it, to describe the current state in present technique field more well.

Those skilled in the art expect as this area, and the The compounds of this invention form that will be used for the certain drug prescription is that it has the needed suitable physical feature of effective prescription (for example water solubility) through selection (for example salt).

Be fit to suck the pharmaceutical composition of (hypogloeeis) administration, comprise lozenge, it comprises The compounds of this invention, in the flavoring base-material, be generally sucrose and gum arabic or tragacanth, and pastille, it comprises this compound, in the inertia base-material, as gelatin and glycerine or sucrose and gum arabic.

The pharmaceutical composition that is fit to administered parenterally comprises the sterile aqueous preparations of The compounds of this invention.These preparations are preferably with the administration of intravenously mode, although also can realize this effect by subcutaneous, intramuscular or intradermal injection.The injectable drug prescription generally is based on the salt solution of injectable Sterile Saline, phosphate buffered, oleagenous suspension or other injectable carrier known in the art, and normally makes it aseptic, and oozes with blood etc.Therefore, the injectable drug prescription can sterile injectable solution or suspension provide, on the nontoxicity parenteral in acceptable diluent or the solvent, comprise 1,3-butyleneglycol, water, Ringer's solution, isotonic sodium chlorrde solution, expressed oil is as synthetic glycerine monoesters or diester, fatty acid is as oleic acid etc.These injectable drug prescriptions are according to known technology, with suitable dispersion or condensing agent and suspension agent allotment.Injectable composition generally is to contain 0.1 to 5%w/w The compounds of this invention.

Solid dosage for the compound oral administration comprises capsule, tablet, pill, powder and particle.For these oral administrations, the pharmaceutically acceptable composition that contains The compounds of this invention, be to form by the vehicle that mixes any common employing, for example N.F,USP MANNITOL of pharmaceutical grade, lactose, starch, starch,pregelatinized, Magnesium Stearate, soluble saccharin, talcum powder, cellulose ether derivative, glucose, gelatin, sucrose, Citrate trianion, Tenox PG etc.These solid pharmaceutical preparations can comprise preparation as well known in the field in this technique, mechanism by any number is to provide the long-term of medicine or to continue to transfer to gi tract, described mechanism includes but not limited to that pH susceptibility disengages formulation, variation pH value based on small intestine, based on the tablet or the capsular slow disintegration of the physical properties of preparation, be detained under one's belt, formulation is to the bio-adhesiveness of intestinal mucosa liner, or active medicine disengages from the enzyme of formulation.

Liquid dosages form for the compound oral administration comprises emulsion, microemulsion, solution, suspension, syrup and elixir, in carrier for example in water, salt solution, the dextrose aqueous solution, glycerine, the ethanol etc., and the optional medicine adjuvant that contains.These compositions also can contain other adjuvants, as wetting, emulsification, suspend, increase sweet, flavoring and perfume compound.

The local dose form of compound comprises ointment, paste, emulsifiable paste, lotion, gel, powder, solution, sprays, inhalation, ophthalmic ointment, eye drop or [, dressing and aerosol through flooding, and can contain suitable conventional additives, as sanitas, the solvent that helps medicine to penetrate, and the softener in ointment and the emulsifiable paste.Partially coated can be once a day or is surpassed once, considers and decides according to general curative.In addition, preferred compound of the present invention can nose in form administration, use mediator in the suitable nose via the part.These preparations also can contain compatible conventional carrier, as emulsifiable paste or ointment base, and the ethanol or the oleyl alcohol that supply lotion to use.These carriers can preparation about 1% to existing up to about 98%, be more typically it and will form up to about 80% preparation.

Percutaneous dosing is also feasible.Be fit to the pharmaceutical composition of percutaneous dosing, can present by discontinuous subsides medicine, be fit to keep contacting closely for a long time with recipient's epidermis.For with form administration through the skin transmission system, dosage yes in whole dosage regimen successive, but not intermittent.These paste medicine and suitably contain compound of the present invention, and described compound is being chosen wantonly in aqueous buffer solution, dissolves and/or is being dispersed in the tackiness agent, or is dispersed in the polymer.The proper concn of active compound is about 1% to 35%, is preferably about 3% to 15%.

For for inhalation, The compounds of this invention can be eligibly with aerosol spray form, transmit from the pumping spraying plant, do not need propellent gas, or from pressure packing or spraying gun, and utilize the transmission of suitable propellent, for example Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, Tetrafluoroethane, heptafluoro-propane, carbonic acid gas or other suitable gas.Under any circumstance, the aerosol spray dose unit can be measured by valve is provided, and with the amount of transmission through metering, so that formedly uses The compounds of this invention through metered dose inhaler (MDI) for reproducibility and controlled way.These suckers, spraying gun or sprayer device are well known in the prior art, and for example (its Fig. 6 particularly, it is to be commercially available RESPIMAT at PCT international publication WO97/12687

The basis of spraying gun); WO94/07607; WO 97/12683; And WO 97/20590, as a reference, and its each part is all introduced for reference with it in full.

Rectal administration can utilize unitary dose suppository to reach, wherein be with compound and low melting point is water-soluble or insoluble solid mixes mutually, mixture as fats, cocoa butter, glycerine gelatin, hydrogenated vegetable oil, different molecular weight polyoxyethylene glycol, or the fatty acid ester of polyoxyethylene glycol, or its analogue.Active compound is generally than small component, frequent about 0.05 to 10 weight %, and rest part is the base-material composition.

In all aforementioned pharmaceutical compositions, The compounds of this invention is to use acceptable carrier or vehicle allotment.Employed carrier or vehicle must be acceptable certainly, and be compatible with other compositions of composition, and harmless to the patient.Carrier or vehicle can be solid or liquid or both, and preferably are mixed with units dosage composition with The compounds of this invention, tablet for example, and it can contain the active compound of 0.05% to 95% weight.These carriers or vehicle comprise inert filler or thinner, tackiness agent, lubricant, disintegrating agent, dissolving retarding agent, absorb accelerator, absorption agent and tinting material.Suitably tackiness agent comprises starch, gelatin, and natural carbohydrate, as glucose or beta lactose, corn sweetener, natural and synthetic colloidal substance is as gum arabic, gum tragacanth or sodium alginate, carboxymethyl cellulose, polyoxyethylene glycol, wax class etc.Lubricant comprises sodium oleate, sodium stearate, Magnesium Stearate, Sodium Benzoate, sodium-acetate, sodium-chlor etc.Disintegrating agent comprises starch, methylcellulose gum, agar, swollen soil, xanthocyte gum (Xanthan gum) etc.

Generally speaking, effectively obeying dosage in the treatment day is to be about 0.001 milligram of The compounds of this invention to about 15 milligrams/kg body weight every day; Be preferably every day about 0.1 milligram to about 10 milligrams/kg body weight; And most preferably be every day about 0.1 milligram to about 1.5 milligrams/kg body weight.For example, to 70 kilograms of people's administration, dosage range is to be about 0.07 milligram to about 1050 milligrams of every day, is preferably about 7.0 milligrams to about 700 milligrams of every day, and most preferably be every day about 7.0 milligrams to about 105 milligrams The compounds of this invention.May need routine dose optimization to a certain degree, to measure optimum take medicine level and mode of administration.

Pharmaceutically acceptable carrier and vehicle are to contain all aforementioned additive etc.

Pharmaceutical preparation embodiment

A. tablet
		Composition	Every consumption (milligram)
Active substance	100
		Lactose	140
W-Gum	240
		Polyvinylpyrolidone (PVP)	15
Magnesium Stearate	5
		Altogether	500

Active substance, lactose and the part W-Gum of fine grinding are mixed.Mixture is sieved, use solution wetted, kneading, the wet granulation and dry of Polyvinylpyrolidone (PVP) in water then.These particles, all the other W-Gums and Magnesium Stearate are sieved, and mix.With the mixture compression, to prepare suitable shape and big or small tablet.

B. tablet
		Composition	The consumption of every tablet (milligram)

Active substance	80
		Lactose	55
W-Gum	190
		Polyvinylpyrolidone (PVP)	15
Magnesium Stearate	2
		Microcrystalline Cellulose	35
Sodium starch glycolate	23
		Altogether	400

Active substance, part W-Gum, lactose, Microcrystalline Cellulose and the Polyvinylpyrolidone (PVP) of fine grinding are mixed.Mixture is sieved, and handle,, be dried and sieve to form particle with all the other W-Gums and water.Add and sneak into sodium starch glycolate and Magnesium Stearate, with the mixture compression, to form the tablet of suitable size.

C. coated tablet
		Composition	The consumption of every tablet (milligram)
Active substance	5
		Lactose	30
W-Gum	41.5
		Polyvinylpyrolidone (PVP)	3
Magnesium Stearate	0.5
		Altogether	90

With active substance, W-Gum, lactose and Polyvinylpyrolidone (PVP) and water thorough mixing, and moistening.With the screen cloth of moist agglomerate propelling movement,, make particle pass through same screens then in about 45 ℃ of dryings through 1 millimeter mesh size.After Magnesium Stearate was sneaked into, the protruding tablet cores that will have 6 millimeters of diameters was compressed in pelleter.With the label of so making apply in a known way comprise basically sugar with talcous dressing.With the coated tablet finished at last with wax polishing.

D. capsule
		Composition	Every capsular consumption (milligram)

Active substance	50
		W-Gum	268.5
Magnesium Stearate	1.5
		Altogether	320

This material is mixed with W-Gum, and moistening with water.Moist agglomerate is sieved, and dry.Dried particles is sieved and mix with Magnesium Stearate.The mixture of finishing at last is packaged in No. 1 hard gelatin capsule.

E. ampoule solution
		Composition	The consumption of per ampoule bottle
Active substance	50 milligrams
		Sodium-chlor	50 milligrams
Water for injection	5 milliliters

Under its own pH, or choose wantonly, make active substance soluble in water, and add sodium-chlor, its grade is oozed at pH5.5 to 6.5 time.The solution that is obtained is filtered, remove pyrogen, and filtrate is transferred in the ampoule under aseptic condition, pass through its sterilization melting sealed then.These ampoules contain 5 milligrams, 25 milligrams and 50 milligrams of active substances.

F. suppository
		Composition	The consumption of every suppository (milligram)
Active substance	50
		Solid fat	1650

Altogether

1700

Make the hard butter fusion.Under 40 ℃, the ground active substance is scattered in wherein equably.Mixture is cooled to 38 ℃, and pours into a little in the refrigerative suppository mould.

G. metered aerosol
		Composition	Consumption

Active substance	0.005
		Sorbitan trioleate	0.1
Single fluoro trichloromethane and methyl chlorofluoride (2: 3)	To 100

This suspension is transferred in the conventional aerosol container with metering valve.The preferred transmission of each spraying 50 microlitre suspension.If need, active substance also can higher dosage metering (for example 0.02 weight %).

H. suck and use powder
		Composition	Consumption
Active substance	1.0 milligram
		Lactose monohydrate	To 25 milligrams

I. suck and use powder
		Composition	Consumption
Active substance	2.0 milligram
		Lactose monohydrate	To 25 milligrams

J. suck and use powder
		Composition	Consumption
Active substance	1.0 milligram
		Lactose monohydrate	To 5 milligrams

K. suck and use powder
		Composition	Consumption

Active substance	2.0 milligram
		Lactose monohydrate	To 5 milligrams

In embodiment H, I, J and K, sucking with powder is with usual way, via single composition is mixed together and makes.

Claims

1. formula (IA) compound

Wherein:

R ¹Be phenyl, randomly replaced by one to three halogen group;

R ²Be hydrogen;

A is N;

B is CH;

C is a chemical bond, and E be chemical bond or-CH ₂-,

D is CR ⁴R ⁵-, R wherein ⁴For-CF ₃, and R ⁵For-OH; And

R ³Be xenyl, phenyl, naphthyl, quinoline, isoquinoline 99.9, indoles, thionaphthene, 2,3-dihydro-1,4-benzo dioxine, 1,3-benzodioxole, OR ⁸, each group is randomly independent to be replaced by one to three substituting group,

Wherein, R ³Each substituting group be C independently ₁-C ₅Alkyl, C ₁-C ₅Alkoxyl group, halogen, trifluoromethyl, amino, wherein nitrogen-atoms is randomly independent of C ₁-C ₅The alkyl list-or two-replace,

R ⁸Be phenyl,

Or its tautomer or salt.

2. compound, it is selected from:

1-biphenyl-3-base-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(3-chloro-phenyl-)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-naphthalene-1-base-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(3-fluorophenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(4-fluorophenyl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1-(4-chloro-phenyl-)-2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl) ethanol;

2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl)-1-quinolyl-4 ethanol;

2,2,2-three fluoro-1-(1H-indoles-4-yl)-1-(1-phenyl-1H-indazole-5-yl) ethanol;

1,1,1-three fluoro-3-phenyl-2-(1-phenyl-1H-indazole-5-yl) propan-2-ol;

2,2,2-three fluoro-1-(1-phenyl-1H-indazole-5-yl)-1-quinolyl-4 ethanol;

1-(2,2-two fluoro-1,3-benzodioxole-4-yl)-2,2,2-three fluoro-1-[1-(4-fluorophenyl)-1H-indazole-5-yl] ethanol

Or its tautomer or salt.

3. pharmaceutical composition, it comprises the compound as claimed in claim 1 or 2 of significant quantity, or its tautomer or salt, and pharmaceutically acceptable vehicle or carrier.

4. compound as claimed in claim 1 or 2 or its tautomer or salt are used for regulating purposes in the pharmaceutical composition of patient's glucocorticoid receptor function in preparation.

5. compound as claimed in claim 1 or 2 or its tautomer or salt are used for treating by the purposes in the pharmaceutical composition of glucocorticoid receptor function institute's disease states mediated or symptom the patient of this treatment of needs in preparation.

6. compound as claimed in claim 1 or 2 or its tautomer or salt are used for purposes in the pharmaceutical composition of the patient of this treatment of needs treatment morbid state or symptom in preparation, and described morbid state or symptom are selected from type ii diabetes, obesity, cardiovascular disorder, hypertension, arteriosclerosis, neurological disease, suprarenal gland and pituitary tumor and glaucoma.

7. compound as claimed in claim 1 or 2 or its tautomer or salt are used for it is characterized by purposes in the pharmaceutical composition of disease of inflammatory, supersensitivity or hyperplasia process in the patient of this treatment of needs treatment in preparation.

8. purposes as claimed in claim 7, wherein disease is selected from: (i) tuberculosis; (ii) rheumatism/autoimmune disease/joint disease; (iii) anaphylactic disease; (iv) vasculitis disease; (v) tetter; (vi) ephrosis; (vii) hepatopathy; (viii) gastrointestinal illness; (x) disease of eye; (xi) disease in ear, nose and larynx (ENT) zone; (xii) neurological disease; (xiii) hematologic disease; (xiv) tumor disease; (xv) endocrinopathy; (xvi) organ and tissue transplantation and graft-vs.-host disease; (xvii) pain of inflammatory origin.

9. purposes as claimed in claim 7, wherein disease is selected from the proctology disease.

10. compound as claimed in claim 1 or 2 or its tautomer or salt and pharmaceutically acceptable glucocorticosteroid are used for treating by the purposes in the pharmaceutical composition of glucocorticoid receptor function institute's disease states mediated or symptom the patient of this treatment of needs in preparation.